The effect of P2Y12 inhibitor pretreatment vs. no pretreatment on major bleeding among patients with NSTE-ACS: an updated meta-analysis and meta-regression pooling 41,548 patients from 11 studies
Authors: Borovac J A , D'Amario D , Schwarz K , Bradaric A , Bozic J , Glavas D ,   Cardiometabolic Research Group
Published: October 2021

Abstract

Background
Recent European Society of Cardiology (ESC) guidelines for the management of non-ST elevation acute coronary syndromes (NSTE-ACS) do not recommend routine pretreatment with P2Y12 inhibitors in patients in whom coronary anatomy is not known and an early invasive management is planned.

Purpose
To investigate the impact of P2Y12 pretreatment vs. no pretreatment on short-term major bleeding events among patients with NSTE-ACS.

Methods
MEDLINE and EMBASE databases were systematically searched to find interventional or observational studies that investigated the use of P2Y12 inhibitors as a pretreatment vs. no pretreatment in NSTE-ACS population. Studies that reported major bleeding events, as adjudicated by study' investigators, during hospitalization or within 30 days since randomization were included. Random-effects meta-analysis was performed with prespecified subgroup analysis concerning more potent P2Y12 inhibitor use and drug-eluting stent (DES) uptake &gt;50%. For the primary analysis, the odds ratio (OR) with 95% confidence intervals (95% CI) were reported. Heterogeneity across studies was inspected by I2 statistic. Meta-regression was performed to assess potential interaction of variables including percutaneous coronary intervention (PCI) receipt, NSTE-ACS subtype, DES uptake &gt;50%, and potent P2Y12 inhibitor use with the primary outcome.

Results
Eleven studies that provided data on major bleeding were included (6 randomized clinical trials, 4 registry-based studies, and 1 prespecified analysis of an RCT) accumulating a total of 41,548 patients with pooled 1366 major bleeding events (871 in the pretreatment and 495 in the no-pretreatment group). Most of the studies were older than 10 years and used clopidogrel as a pretreatment while the average rate of PCI receipt was 78.2%. Low-to-moderate heterogeneity was detected across studies. Pretreatment with P2Y12 inhibitors increased the likelihood of major bleeding (OR 1.245, 95% CI 1.092–1.419) across all studies analyzed while in contemporary NSTE-ACS cohorts with high penetration of DES platforms and agents more potent than clopidogrel, this effect was borderline (OR 1.241, 95% CI 0.901–1.709 – Figure 1 and OR 1.443, 95% CI 0.742–2.807 – Figure 2, respectively). Of all variables, the use of potent P2Y12 inhibitors was independently associated with the increase of major bleeding events (coefficient 0.743, 95% CI 0.133–1.354, P=0.017).

Conclusions
Our updated results show that P2Y12 pretreatment was associated with the increased likelihood of major bleeding with this effect diminished in contemporary NSTE-ACS cohorts, although the latter could be attributed to presence of heterogeneity. The use of potent P2Y12 agents was a significant modifier of major bleeding. Taken together, routine pretreatment with P2Y12 inhibitors in NSTE-ACS increases the likelihood of major bleeding with this effect generally being enhanced by potent antiaggregation used, regardless of pretreatment utilization.

Funding Acknowledgement
Type of funding sources: None. Figure 1. Major bleeding and DES useFigure 2. Major bleeding and P2Y12 type