IMPORTANCE Very short mandatory dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with a drug-eluting stent may be an attractive option. OBJECTIVE To test the hypothesis of noninferiority of 1 month of DAPT compared with standard 12 months of DAPT for a composite end point of cardiovascular and bleeding events. DESIGN, SETTING, AND PARTICIPANTS Multicenter, open-label, randomized clinical trial enrolling 3045 patients who underwent PCI at 90 hospitals in Japan from December 2015 through December 2017. Final 1-year clinical follow-up was completed in January 2019. INTERVENTIONS Patients were randomized either to 1 month of DAPT followed by clopidogrel monotherapy (n=1523) or to 12 months of DAPT with aspirin and clopidogrel (n=1522). MAIN OUTCOMES AND MEASURES The primary end point was a composite of cardiovascular death, myocardial infarction (MI), ischemic or hemorrhagic stroke, definite stent thrombosis, or major or minor bleeding at 12 months, with a relative noninferiority margin of 50%. The major secondary cardiovascular end point was a composite of cardiovascular death, MI, ischemic or hemorrhagic stroke, or definite stent thrombosis and the major secondary bleeding end point was major or minor bleeding. RESULTS Among 3045 patients randomized, 36 withdrew consent; of 3009 remaining, 2974 (99%) completed the trial. One-month DAPT was both noninferior and superior to 12-month DAPT for the primary end point, occurring in 2.36% with 1-month DAPT and 3.70% with 12-month DAPT (absolute difference, −1.34% [95% CI, −2.57% to −0.11%]; hazard ratio [HR], 0.64 [95% CI, 0.42-0.98]), meeting criteria for noninferiority (P < .001) and for superiority (P = .04). The major secondary cardiovascular end point occurred in 1.96% with 1-month DAPT and 2.51% with 12-month DAPT (absolute difference, −0.55% [95% CI, −1.62% to 0.52%]; HR, 0.79 [95% CI, 0.49-1.29]), meeting criteria for noninferiority (P = .005) but not for superiority (P = .34). The major secondary bleeding end point occurred in 0.41% with 1-month DAPT and 1.54% with 12-month DAPT (absolute difference, −1.13% [95% CI, −1.84% to −0.42%]; HR, 0.26 [95% CI, 0.11-0.64]; P = .004 for superiority). CONCLUSIONS AND RELEVANCE Among patients undergoing PCI, 1 month of DAPT followed by clopidogrel monotherapy, compared with 12 months of DAPT with aspirin and clopidogrel, resulted in a significantly lower rate of a composite of cardiovascular and bleeding events, meeting criteria for both noninferiority and superiority. These findings suggest that a shorter duration of DAPT may provide benefit, although given study limitations, additional research is needed in other populations.

Background-There is a scarcity of long-term data from large-scale drug-eluting stent registries with a large enough sample to evaluate low-frequency events such as stent thrombosis (ST). Methods and Results-Five-year outcomes were evaluated in 12 812 consecutive patients undergoing sirolimus-eluting stent (SES) implantation in the j-Cypher registry. Cumulative incidence of definite ST was low (30 day, 0.3%; 1 year, 0.6%; and 5 years, 1.6%). However, late and very late ST continued to occur without attenuation up to 5 years after sirolimus-eluting stent implantation (0.26%/y). Cumulative incidence of target lesion revascularization within the first year was low (7.3%). However, late target lesion revascularization beyond 1 year also continued to occur without attenuation up to 5 years (2.2%/y). Independent risk factors of ST were completely different according to the timing of ST onset, suggesting the presence of different pathophysiological mechanisms of ST according to the timing of ST onset: acute coronary syndrome and target of proximal left anterior descending coronary artery for early ST; side-branch stenting, diabetes mellitus, and end-stage renal disease with or without hemodialysis for late ST; and current smoking and total stent length Ͼ28 mm for very late ST. Independent risk factors of late target lesion revascularization beyond 1 year were generally similar to those risk factors identified for early target lesion revascularization. Conclusion-Late adverse events such as very late ST and late target lesion revascularization are continuous hazards, lasting at least up to 5 years after implantation of the first-generation drug-eluting stents (sirolimus-eluting stents), which should be the targets for developing improved coronary stents. (Circulation. 2012;125:584-591.)Key Words: coronary artery disease Ⅲ prognosis Ⅲ restenosis Ⅲ stents Ⅲ thrombosis C oronary drug-eluting stents (DES) have been used widely in clinical practice. Results from several randomized, controlled trials and registries comparing midterm (2-3 years) outcome between bare metal stents (BMS) and DES are generally reassuring for DES use with a marked reduction of target lesion revascularization (TLR) without major safety issues. 1,2 However, in contrast to the clinical course after BMS implantation, 3 late adverse events such as very late stent thrombosis (VLST) and late TLR are reported to continue occurring beyond 1 year up to 3 to 4 years after DES implantation. 4,5 Despite lingering concerns about DES-related late adverse events, there is a scarcity of longer-term data from large-scale DES registries with adequate statistical power to evaluate lowfrequency events such as stent thrombosis (ST). Editorial see p 562 Clinical Perspective on p 591In the present report, we comprehensively evaluated 5-year clinical outcome after sirolimus-eluting stent (SES) implanContinuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz. Received May 31, 2011; accepted November 7, 2011 Met...

Macropinocytosis, a fluid-phase endocytosis, is a crucial pathway for antigen uptake and presentation in macrophages. We attempted to characterise the activation and deactivation of a small GTPase molecular switch, Rac1, in macropinocytosis using microscopic photo-manipulation. Expression of genetically encoded photoactivatable-Rac1 (PA-Rac1) in RAW264 macrophages enabled the local, reversible control of macropinocytosis using blue laser irradiation. Marked membrane ruffling and unclosed pre-macropinosomes were observed in the irradiated region of macrophages under the persistent activation of PA-Rac1. Although phosphatidylinositol 4,5-bisphosphate and actin were also localised to this region, the recruitment of maturating endosome markers, such as phosphatidylinositol 3-phosphate and Rab21, was restricted until PA-Rac1 deactivation. After deactivating PA-Rac1 by ceasing irradiation, membrane ruffling immediately receded, and the macropinosomes acquired maturation markers. These data suggest that activation of Rac1 is sufficient to induce membrane ruffling and macropinocytic cup formation, but subsequent deactivation of Rac1 is required for macropinosome closure and further maturation.

Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and solutes are internalized into cells. Macropinocytosis starts with the formation of membrane ruffles at the plasma membrane and ends with their closure. The transient and sequential emergence of phosphoinositides PI(3,4,5)P 3 and PI(3,4) P 2 in the membrane ruffles is essential for macropinocytosis. By making use of information in the Caenorhabditis elegans mutants defective in fluid-phase endocytosis, we found that mammalian phosphoinositide phosphatase MTMR6 that dephosphorylates PI(3)P to PI, and its binding partner MTMR9, are required for macropinocytosis. INPP4B, which dephosphorylates PI(3,4)P 2 to PI(3)P, was also found to be essential for macropinocytosis. These phosphatases operate after the formation of membrane ruffles to complete macropinocytosis. Finally, we showed that KCa3.1, a Ca 2+ -activated K + channel that is activated by PI(3)P, is required for macropinocytosis. We propose that the sequential breakdown of PI(3,4,5)P 3 → PI(3,4)P 2 → PI(3)P → PI controls macropinocytosis through specific effectors of the intermediate phosphoinositides.

Six months of DAPT was not inferior to 18 months of DAPT following implantation of a DES with a biodegradable abluminal coating. However, this result needs to be interpreted with caution given the open-label design and wide noninferiority margin of the present study. (Nobori Dual Antiplatelet Therapy as Appropriate Duration [NIPPON]; NCT01514227).