Background New-generation drug-eluting stents (DES) have been mostly investigated by means of head-to-head non-inferiority trials, which typically showed comparable efficacy and greater safety as compared with early-generation DES. Evidence related to new-generation DES versus bare-metal stents (BMS) is more limited, and there remain uncertainties on their comparative safety profile. Methods We performed an individual patient data (IPD) meta-analysis of randomized trials comparing new-generation DES with BMS among patients undergoing percutaneous coronary intervention. The protocol of the study was registered in PROSPERO (CRD42017060520). The primary outcome was the composite of cardiac death or myocardial infarction. Data were pooled in a one-stage random effects metaanalysis and examined at maximum follow-up and with 1-year landmark. Risk estimates are reported as hazard ratio (HR) with 95% confidence intervals (95%CI). Findings We obtained IPD data from 20 randomized trials including a total of 26,616 patients, with 3•2±1•8 years mean follow-up. The primary outcome occurred in fewer patients in the DES group than in the BMS group (HR 0•84, 95%CI 0•78 to 0•90, P<0•001) owing to lower risk of myocardial infarction (HR 0•79, 95%CI 0•71 to 0•88, P<0•001) and weaker evidence for a possible cardiac mortality benefit (HR 0•89, 95%CI 0•78 to 1•01, P=0•075). All-cause death was unaffected (HR with DES, 0•96, 95%CI 0•88 to 1•05, P=0•358), but DES reduced the risk of definite stent thrombosis (HR 0•63, 95%CI 0•50 to 0•80, P<0•001) and targetvessel revascularization (HR 0•55, 95%CI 0•50 to 0•60, P<0•001). There was evidence for a time-dependent treatment effect, with DES being associated with lower risks of the primary outcome during the first year followed by a null effect in the subsequent years. Interpretation New-generation DES instead of BMS were associated with sustained reduction of cardiac death or myocardial infarction owing to lower event rates within the first year without offsetting effects thereafter.

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Programmed necrosis (necroptosis), a newly discovered form of cell death, is mediated by receptor-interacting protein 1 (RIP1) and plays a pivotal role after myocardial, renal, and cerebral ischemia-reperfusion (I/R). The relevance of necroptosis in the postischemic liver remains, however, unclear. The aim of this study was to analyze the role of programed necrosis during hepatic I/R. C57BL6 mice were subjected to warm hepatic I/R (90 min/240 min). The animals were pretreated with either the RIP1 inhibitor necrostatin-1 (Nec-1, 3.5 μg kg) or vehicle (Nec-1inactive, 3.5 μg kg) administered systemically before ischemia. Sham-operated animals served as controls (n = 6 each group). The inflammatory response was evaluated by intravital microscopy. The hepatic transaminases alanine aminotransferase/aspartate aminotransferase in plasma as well as the activity of caspase-3 in tissue were determined as markers of hepatocellular injury. Leukocyte recruitment to the liver, sinusoidal perfusion failure, as well as the transaminase activities were strongly increased on I/R as compared with the sham-operated mice. Inhibition of the RIP1-dependent pathway with Nec-1, however, did not attenuate I/R-induced leukocyte migration, perfusion failure, and hepatocellular injury. Western blot analysis showed a baseline RIP1 expression in livers from sham-operated mice, whereas RIP1 expression was not detectable in both Nec-1-treated and vehicle-treated I/R group. Caspase-3 activity was significantly elevated after I/R in both postischemic groups. Our in vivo data show that RIP1-mediated necroptosis is not present in the postischemic liver and that I/R-induced caspase activation is associated with loss of RIP1 expression. Because caspases are able to cleave RIP1, we hypothesize that I/R-triggered caspase activation negatively regulates necroptosis and, thereby, determines apoptosis as a preferred route of cell death after hepatic I/R.

Our in vivo data suggest PAR-4 as a potential target for future therapeutic strategies against platelet-mediated liver injury on transplantation.

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