<h2>Pretreatment with P2Y12 inhibitors in patients with nonST-segment elevation acute coronary syndrome: A meta-analysis.</h2>

In this meta-analysis, clopidogrel pretreatment was associated with significantly lower risk of mortality, major adverse cardiovascular events (MACE), myocardial infarction (MI), death, and revascularization without increase in risk of major bleeding in nonST-segment elevation acute coronary syndrome (NSTE-ACS) patients. However, prasugrel or ticagrelor pretreatment lacked ischemic protection and caused major bleeding events.

<h2>Key Takeaway</h2>
<ul>
 <li>This meta-analysis comparing pretreatment with P2Y12 inhibitors with no pretreatment in patients with NSTE-ACS from nine studies demonstrated that: 
 <ul>
 <li>P2Y12 inhibitor pretreatment was associated with lower death from any cause without increasing the risk of major bleeding with no distinction in MI, revascularization and MACE</li>
 <li>Clopidogrel pretreatment subgroup was significantly associated with lower incidence of mortality, MACE, MI, and revascularization without increasing major bleeding</li>
 <li>Prasugrel or ticagrelor pretreatment subgroup was associated with no significant difference in mortality, MACE, MI or revascularization, whereas major bleeding events were significantly increased</li>
 <li>Lower mortality and ischemic protection were observed in non- randomized controlled trials (RCTs) vs RCTs</li>
 </ul></li>
</ul>

<h2>Why This Matters</h2>
<ul>
 <li>P2Y12 receptor inhibitor loading (300 mg clopidogrel) before percutaneous coronary intervention (PCI) is found to reduce MACE but slightly increase bleeding events 
 <ul>
 <li>However, large-scale RCTs of clopidogrel pretreatment are lacking</li>
 </ul></li>
 <li>Current RCTs for prasugrel and ticagrelor do not recommend pretreatment, as they do not reduce ischemic events but increase the risk of major bleeding.</li>
 <li>In the era of prasugrel and ticagrelor, the optimal timing of P2Y12 receptor inhibitor administration remains controversial.</li>
 <li>This meta-analysis compared pretreatment with P2Y12 inhibitors with no pretreatment in patients with NSTE-ACS.</li>
</ul>

<h2>Study Design</h2>
<ul>
 <li>This meta-analysis included trials meeting following criteria: Studies with &gt;50% of patients with NSTE-ACS; studies comparing pretreatment with P2Y12 inhibitor with no pretreatment; observational or randomized studies; studies with data on loading dose and timing of P2Y12 inhibitors were available; data reporting any data of interest, including at least any cause mortality, major bleeding</li>
 <li>Excluded trials: Ongoing and no control group studies and duplicate reports</li>
 <li>Primary efficacy and safety endpoint: Death from any cause and major bleeding</li>
 <li>Secondary endpoint: MACEs, MI and revascularization</li>
</ul>

<h2>Key Results</h2>
Characteristics of the included studies
<ul>
 <li>This meta-analysis included nine studies (2 RCTs, 2 post hoc analyses of RCTs and 5 non-RCTs).</li>
 <li>Pretreatment with prasugrel or ticagrelor was included in 2 studies, pretreatment with 3 P2Y12 inhibitors (clopidogrel, prasugrel, and ticagrelor) in one study, and pretreatment with clopidogrel in 6 studies.</li>
 <li>Of the 94,506 NSTE-ACS patients enrolled, 80,272 patients were pretreated with P2Y12 inhibitor.</li>
 <li>In total 51,922 patients (55.6%) were treated with clopidogrel, and 41,389 (44.4%) patients were treated with prasugrel or ticagrelor.</li>
</ul>

Impact on primary outcomes
<ul>
 <li>Pretreatment before coronary angiography (CAG) in NSTE-ACS patients was associated with 
 <ul>
 <li>Significant lower incidence of mortality (odds ratio [OR] = 0.62, 95% confidence interval, [CI]: 0.53–0.72, P &lt;0.00001)</li>
 <li>No significant difference in the incidence of major bleeding (OR = 1.02, 95% CI: 0.80–1.30, P = 0.89)</li>
 </ul></li>
</ul>

Impact on MACE, MI, and revascularization
<ul>
 <li>No difference was noticed between the pretreatment group and no pretreatment group 
 <ul>
 <li>MACE: OR = 0.83, 95% CI: 0.68–1.01, P = 0.07</li>
 <li>MI: OR = 0.74, 95% CI: 0.54–1.00, P = 0.05</li>
 <li>Revascularization: OR = 0.82, 95% CI: 0.67–1.00, P = 0.05</li>
 </ul></li>
</ul>

Subgroup analyses:&nbsp;Prasugrel or ticagrelor vs clopidogrel
<ul>
 <li>Prasugrel or ticagrelor pretreatment was associated with: 
 <ul>
 <li>No striking differences in mortality (OR = 0.70, 95% CI: 0.31–1.59, P = 0.40), MACE, MI, and revascularization</li>
 <li>Significantly increased major bleeding events (OR = 1.67, 95% CI: 1.10–2.54, P = 0.02)</li>
 </ul></li>
 <li>Clopidogrel pretreatment was associated with lower incidence of mortality (OR = 0.61, 95% CI: 0.52–0.72, P &lt;0.0001), MACE, MI, and revascularization without increasing major bleeding.</li>
</ul>

Sensitivity analysis and reporting bias
<ul>
 <li>Results remained unchanged post excluding study with largest number of patients.</li>
 <li>No obvious heterogeneity in research results of different era* was observed.</li>
</ul>

<h2>Limitations</h2>
<ul>
 <li>Most included studies were non RCTs with inherent biases and confusions</li>
 <li>Obvious heterogeneity in MI and MACE was observed</li>
 <li>Pretreatment definition as well as the time from P2Y12 inhibitor load to PCI differed in various studies.</li>
 <li>The analysis of the potency of P2Y12 was limited due to a lack of data</li>
</ul>
*The relevant research results before (before 2011) and after the change (after 2011) For additional details, please refer to the source publication,&nbsp;<a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC9259160/" target="_blank">Yan L et al.</a>

Reference

Ticagrelor vs Clopidogrel in high bleeding risk patients with ACS

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Ticagrelor vs Clopidogrel in high bleeding risk patients with ACS