Effectiveness and Safety of P2Y12 Inhibitor Pretreatment for Primary PCI in STEMI: Systematic Review and Meta-analysis

Supplemental Digital Content is Available in the Text. Abstract: Dual antiplatelet therapy with aspirin and P2Y12 inhibitors in patients with ST-segment elevation myocardial infarction (STEMI) has been shown to be associated with better outcomes. Yet, there is uncertainty regarding the optimal timing for its initiation. We performed a systematic review and meta-analysis of evidence on pretreatment with P2Y12 inhibitors in combination with aspirin in patients with STEMI undergoing primary percutaneous coronary intervention (PCI). We performed a systematic search of electronic databases PubMed, CENTRAL, and Scopus until April 2022. Studies were eligible if they compared P2Y12 inhibitor upstream administration with downstream use in patients with STEMI submitted to PCI. Studies with patients receiving fibrinolysis or medical therapy only were excluded. Outcomes were assessed at the shortest follow-up available. Of 2491 articles, 3 RCT and 16 non-RCT studies were included, with a total of 79,300 patients (66.1% pretreated, 66.0% treated with clopidogrel). Pretreatment was associated with reduction in definite stent thrombosis (odds ratio [OR] 0.61 [0.38–0.98]), all-cause death (OR 0.77 [0.60–0.97]), and cardiogenic shock (OR 0.60 [0.48–0.75]). It was also associated with a lower incidence of thrombolysis in myocardial infarction flow <3 pre-PCI (OR 0.78 [0.67–0.92]). However, incidence of recurrent MI was not significantly reduced (OR 0.93 [0.57–1.52]). Regarding safety, pretreatment was not associated with a higher risk of major bleeding events (OR 0.83 [0.75–0.92]). Pretreatment with dual antiplatelet therapy, including a P2Y12 inhibitor, was associated with better pre-PCI coronary perfusion, lower incidence of definite stent thrombosis, cardiogenic shock, and, possibly, all-cause mortality with no sign of potential harm encountered.


INTRODUCTION
ST-segment elevation myocardial infarction (STEMI) results from the formation of an occlusive (or nearocclusive) arterial thrombus in a coronary artery usually after the rupture of an atherosclerotic plaque.To limit the damaging consequences of this occurrence, 1 of the primary therapeutic goals is to decrease the duration of ischemia.This is achieved by the recanalization of the infarct-related artery.From a pathophysiologic standpoint, it is known that the central process that leads to thrombus formation results from platelet activation and aggregation.This period of myocardial ischemia represents the critical moment where early administration of a drug that blocks this process may have an important effect in the achievement of recanalization of the infarct-related artery, possibly improving outcomes. 1retreatment or upstream treatment strategy in the setting of a myocardial infarction comprises a variety of common clinical scenarios where the drug is given before knowledge of coronary anatomy-in the ambulance, in the emergency department, in a spoke hospital, or in the hub hospital before coronary angiography and/or percutaneous coronary intervention (PCI). 2 However, downstream treatment strategy refers to the administration of second antiplatelet after knowledge of said anatomy-before PCI or after the procedure.Even though the European Society of Cardiology and American College of Cardiology guidelines for STEMI recommend the early administration of a P2Y12 inhibitor, they raise doubts regarding the optimal timing for this intervention. 3,4Actually, evidence for this recommendation is weak, being mainly based on the methodology of studies that showed a benefit of these medications, rather than from studies directly comparing the timing of its administration. 5,6As a matter of fact, no randomized clinical trial has demonstrated significant mortality benefit of early administration of this second antiplatelet, in comparison to its administration after knowing coronary anatomy.Only 1 large RCT has been published concerning this subject, which showed no mortality benefit, even though definite stent thrombosis was reduced. 7Nevertheless, some doubts have been raised regarding these results, because the median time between the 2 loading strategies was only 31 minutes.Besides being a very short interval, which may not leave much space to allow meaningful differences between groups, it is also not representative of STEMI fast transfer protocol networks.Even though these results may be applicable to faster transfer networks, outcomes could be different when transfer times are longer.
Yet, the use of a second antiplatelet drug before defining coronary anatomy is a double-edged sword because the risk-benefit may vary significantly between patients.On one hand, there is the potential benefit of reducing ischemic time, and thrombotic complications, including periprocedural myocardial infarction or early stent thrombosis.However, it raises concerns of higher procedural bleeding risk, especially if a femoral approach is used or a coronary artery bypass graft is needed. 8,9Also, there is the possibility of a false activation where the final diagnosis proves to be different, such as aortic dissection, with the antiplatelet being potentially harmful or undesired. 2This is particularly important because the routine upstream use of other potent antiplatelet therapies, namely the glycoprotein IIb/IIIa inhibitors, has been shown to increase the risk of bleeding events without demonstrated benefit to offer. 3n this background, and facing the existing conflicting data and opinions, we conducted a systematic review with meta-analysis evaluating whether pretreatment with P2Y12 inhibitors in combination with aspirin, is beneficial, in efficacy and safety outcomes, in patients with STEMI who underwent primary PCI.

Search of Studies and Data Extraction
We conducted this meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis recommendations. 10e performed a systematic search of electronic databases PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus until April of 2022 with the following search query: ("p2y12 inhibitor" OR prasugrel OR ticagrelor OR clopidogrel) AND (STEMI) AND (upstream OR time OR timing OR pretreatment).Two authors (J.P. and D.G.) independently assessed titles, abstracts, and full texts, when appropriate, for eligibility and data extraction.Disagreements were resolved by consensus or, if necessary, by a third author (J.F.).Studies were considered eligible if they were (1) comparing P2Y12 inhibitor upstream administration (in the ambulance or in a hospital without the possibility of performing PCI) with downstream treatment (in-hospital with catheterization laboratory); (2) patients enrolled for STEMI and be submitted to primary PCI.We excluded studies that included patients treated with fibrinolysis or medical therapy only.Data extraction was performed by both authors into a previously defined form and registered in PROSPERO (ID: CRD42022326249).The quality of the included observational studies and randomized clinical trials (RCTs) was assessed using the Newcastle-Ottawa quality assessment scale and RoB 2.0 tool, respectively (see Figure S1, Supplemental Digital Content 1, http://links.lww.com/JCVP/A975 and Table S1, Supplemental Digital Content 2, http://links.lww.com/JCVP/A978).

Clinical Outcomes
For analysis purposes, the following outcomes were considered: all-cause mortality; recurrent MI; definite stent thrombosis; no-reflow phenomenon; thrombolysis in myocardial infarction (TIMI) flow grade before PCI; TIMI flow grade after PCI; cardiogenic shock; and major bleeding event.Outcome events were defined based on the definition used in each original study and assessed at the shortest follow-up available (see Table S2, Supplemental Digital Content 3, http://links.lww.com/JCVP/A979 and Table S3, Supplemental Digital Content 4, http://links.lww.com/JCVP/A980).
Sensitivity analyses were run for the more potent P2Y12 inhibitors and for outcomes at 30 days follow-up.

Statistical Analysis
The extracted data were analyzed using the opensource statistical software Review Manager (RevMan), V.5.4.1 (The Cochrane Collaboration, 2020) software to aggregate the meta-analysis results, and ProMeta 3 software.The effect size was estimated using a random-effect model as an odds ratio (OR) and a relative 95% confidence interval (CI).This model was chosen considering the demographic and clinical heterogeneity across the different studies included in our analysis.Heterogeneity across studies was assessed by I 2 using Cochran's Q test, which estimates the proportion of variation in effect size attributable to interstudy heterogeneity, given that an I 2 test equal to or higher than 50% determines significant heterogeneity (14).Two sensitivity analyses were performed to stratify outcomes by follow-up time (in hospital and 30-days) and P2Y12 inhibitor used.Publication bias was assessed by graphical inspection of funnel plots and by Egger's linear regression test.

Included Studies and Patient Characteristics
A total of 2491 studies were identified through database searching.After removing duplicates and applying inclusion and exclusion criteria, 37 articles were assessed for full-text screening, with 19 studies being included in the final analysis (Fig. 1).Overall, 3 RCTs, 2 post-hoc analyses of RCT, 3 prospective observational, 10 observational registries, and 1 retrospective observational study were included.A summary of study characteristics is presented in Table 1 and Supplemental Digital Content 5 (see Table S4, http:// links.lww.com/JCVP/A981).
Of 79,300 patients studied, 66.1% received pretreatment and 66.0% were treated with clopidogrel.Looking at real-world data (after the exclusion of patients included in RCTs and propensity-matched studies), we found a similar proportion of patients receiving upstream administration of P2Y12 inhibitor (66.6%).Further clinical characteristics of each study's population are described in Supplemental Digital Content 3 (see Table S2, http://links.lww.com/JCVP/A979).
Concerning the duration of the follow-up for each studied outcome, most studies reported in-hospital outcomes, with only 9 studies reporting some of the outcomes at 30 days.The only exception was the occurrence of definite stent thrombosis, with 2 studies reporting outcomes at 24 and 48 hours of follow-up.There was also heterogeneity regarding time difference for drug administration between groups of each trial, varying from a mean time difference of 31 minutes up to 91 minutes. 28,29tcomes Mortality was reported in 15 studies, with the occurrence of a total of 3410 deaths.There was a lower risk for allcause mortality in the pretreatment arm (OR 0.77 [0.60-0.97])with significant heterogeneity (I 2 = 64%, Fig. 2).Pretreatment was also associated with a lower risk of lower TIMI flow grade before PCI (OR 0.78 [0.67-0.92])with significant heterogeneity between studies (I 2 = 83%, see Figure S2, Supplemental Digital Content 6, http://links.lww.com/JCVP/A976).
Regarding safety outcomes, pretreatment was not associated with a higher risk of major bleeding events (OR 0.83 [0.75-0.92])with very-low heterogeneity between groups (I 2 = 0%, Fig. 6).

Sensitivity Analysis
When studying outcomes for patients treated with the more potent P2Y12 inhibitors ticagrelor or prasugrel (Fig. 7), we found that pretreatment maintained benefit in definite stent thrombosis (OR 0.29 [0.12-0.73]).However, results turned neutral for all-cause mortality (OR 0.90 [0.44-1.85])and major bleeding events (OR 0.92 [0.59-1.46]).Myocardial infarction and no-reflow outcomes also remained neutral.Cardiogenic shock analysis was not possible because no study specified this outcome according to the type of P2Y12 inhibitor.
When studying outcomes at 30 days, even though pretreatment was associated with a lower incidence of definite stent thrombosis (OR 0.46 [0.23-0.90]), it lost association with death of any cause (OR 0.79 [0.59-1.06]).

Risk of Bias
Risk of bias evaluation for RCTs and nonrandomized studies is reported in Supplemental Digital Content 1 (see Figure S1, http://links.lww.com/JCVP/A975) and Supplemental Digital Content 2 (see Table S1, http:// links.lww.com/JCVP/A978).Funnel plots and Egger's linear regression tests identified a potential publication bias for TIMI flow grade before PCI (P = 0.027).No other publication biases were identified.

DISCUSSION
In this study, we present the results of the largest metaanalysis published to date comparing pretreatment with DAPT versus downstream treatment for patients with STEMI who underwent PCI.Pretreatment was associated with significant reductions in stent thrombosis, cardiogenic shock, and all-cause death.It was also associated with better coronary perfusion before PCI.In addition, pretreatment seems to be safe, because it was not associated with a higher risk for major bleeding events.
It is clear that the sooner a patient with a STEMI gets revascularized, the better the outcome. 3Pathophysiologically, to preserve myocardial viability, the early use of antiplatelet therapy is a logical option to try to improve coronary perfusion while the patient is being transferred to a catheterization laboratory.In the last 2 decades, P2Y12 inhibitors emerged as a potential complement for these patients, enabling a more complete antiplatelet activity.However, some concerns regarding its safety and overall benefit have come up, because these medications raise bleeding risk and have a fairly long half-life time.
In this meta-analysis of 18 studies and a population of nearly 80,000 patients, we found that pretreatment is associated with better pre-PCI coronary perfusion, demonstrated by the higher TIMI flow grade in pretreated patients.Better coronary perfusion in STEMI is a surrogate marker for greater myocardial preservation, which validates our finding of lower risk for developing in-hospital cardiogenic shock in the cohort of pretreated patients.
Pretreatment was also associated with a very significant reduction in definite stent thrombosis.This finding was not only consistent across the great majority of integrated studies, but was also independent of the studied follow-up and type of P2Y12 inhibitor. 29Looking closer at the studies with neutral results for this outcome, despite there being no available data to do a deeper analysis regarding the TRITON trial, we found that the other studies had several factors that may justify these findings-both were observational; both had a statistically significant higher use of IIb/IIIa inhibitors in the downstream arm; and both had an overall more complex coronary disease in the pretreatment arm.This study also shows a possible significant reduction in the incidence of cardiogenic shock in pretreated patients.Despite all studies pointing in the direction of potential benefit, this test showed significant heterogeneity, which may be related to the low number of studies included.Moreover, only non-RCT studies were included in this analysis.In any case, the hypothesis of a potential benefit from this strategy in reducing the incidence of cardiogenic shock seems plausible.
Overall, these listed factors may justify the mortality benefit found in patients pretreated with P2Y12-receptor inhibitors.Nonetheless, these results should be interpreted cautiously because some uncertainties may still arise.First, most previous studies reported neutral results regarding this outcome. 25,29Second, in our sensitivity analyses (potent P2Y12-receptor inhibitors; follow-up at 30 days), mortality results were neutral.Third, despite the demonstration of better perfusion, lower incidence of cardiogenic shock, and stent thrombosis, there was no significant reduction in the incidence of myocardial infarction, which would be expected to be one of the drivers of worse survival.Fourth, the maximum pharmacodynamic effect of clopidogrel is only reached 2-4 hours after its oral administration, which theoretically could compromise the benefit of pre-administration.However, pharmacodynamic studies show around 50% of maximum inhibitory effect on platelet aggregation with 5 mmol/L only 30 minutes after oral administration. 30Finally, we found significant heterogeneity between studies.This may have been because of low rates of mortality in each study, raising the probability of random imbalances between groups.In summary, we hypothesize that there may be a potential benefit in mortality to be gained from pretreatment, but no definitive conclusions should be drawn regarding this subject.
Another of the main concerns about this approach is its associated bleeding risk.Remarkably, our study found that the use of pretreatment was associated with a lower risk for major bleeding events.The main reason to justify this finding is the fact that there was a significantly higher use of bailout GP-IIbIIIa in the downstream treatment cohort in several studies, drugs usually associated with increased risk of bleeding. 11,13,16,20,22,27Also, the strategy chosen by the operator regarding medical and invasive therapy may be influenced by the presence of pretreatment.This carries the risk of bias, because most included studies are observational and nonblinded.However, despite showing very low heterogeneity between studies, these results were not replicated in sensitivity analysis, showing a neutral result on that evaluation.Nevertheless, these findings support the safety of this approach and minimize concerns regarding its use.
Concerning the subgroup of more potent P2Y12 inhibitors, neutral results for all outcomes except definitive stent thrombosis mortality may be justified by the fundamental pharmacologic differences between these drugs and clopidogrel.Because they are more potent and have a faster onset of action, this may diminish the benefit to be gained by pretreatment.Moreover, the marked reduction in the number of studies included in this sensitivity analysis may contribute to the result.
It seems clear that pretreatment reduces the risk of definite stent thrombosis and may also reduce other clinical outcomes such as cardiogenic shock.Moreover, these results are also reassuring regarding safety outcomes, suggesting that bleeding risk is not higher in patients who are pretreated.Some doubts remain regarding other outcomes, even though the all-cause mortality benefit seems plausible.Nevertheless, the potential benefits seem to largely outweigh the harms, because no sign of damage was raised by this meta-analysis.As such, we believe pretreatment should be the preferential approach regarding patients with the diagnosis of STEMI.

Limitations
Our study has some limitations that should be acknowledged.The main limitation of this analysis is that most of the data are derived from observational studies that have inherent limitations that are well known.Moreover, we had no access to individual patient data, and, therefore, we conducted a study-level analysis.The outcome definitions were somewhat heterogeneous across the included studies, introducing potential bias in our analysis.Also, there were differences between studies in antiplatelet strategies, times to PCI, preloading doses, and types of stents used.The use of shortest follow-up for each outcome raises heterogeneity between studies.However, it overcomes the limitation of study exclusion driven by specific duration of follow-up.Many of these studies are related to clopidogrel, which is not the currently recommended first-line treatment according to the 2017 ESC guidelines.Also, the use of IIb/IIIa inhibitors reported in many of the included trials is significantly higher than the use in modern interventional practice.Furthermore, heterogeneities across studies for mortality, TIMI flow-grade before PCI, cardiogenic shock, myocardial infarction, and no-reflow phenomenon were significant.The presence of publication bias for TIMI flow grade before PCI is also a limitation.

CONCLUSION
Pretreatment with P2Y12 inhibitor before PCI was associated with a lower risk of definite stent thrombosis, lower risk of cardiogenic shock risk, and better pre-PCI coronary perfusion.Furthermore, our findings raise the possibility of potential mortality benefits in this cohort.In addition, no sign of potential harm from this approach was encountered in pretreated patients.These results raise the hypothesis of a potential benefit from upstream treatment and support the conduction of a large clinical trial.

FIGURE 1 .
FIGURE 1. Flow diagram of the research strategy and study selection process.

FIGURE 2 .
FIGURE 2. Forest plot comparing pretreatment versus.downstream treatment regarding all-cause mortality.

FIGURE 7 .
FIGURE 7. Forest plots of the sensitivity analysis for more potent P2Y12 inhibitors in pretreatment versus downstream treatment for the following events: (A) All-cause death; (B) definitive stent thrombosis; and (C) major bleeding events.

TABLE 1 .
Characteristics of Studies Included in the Meta-Analysis