| Part I.Prophylactic Rivaroxaban Therapy for Left Ventricular Thrombus After Anterior ST-Segment Elevation Myocardial Infarction:an open-label,superiority,single-center,randomized controlled trialObjective:Anterior ST-segment elevation myocardial infarction(STEMI)is associated with an increased risk of left ventricular thrombus(LVT)formation.The contemporary role of prophylactic rivaroxaban therapy remains unclear.The aim of this study was to investigate the effects of rivaroxaban on left ventricle thromboprophylaxis in patients with anterior STEMI.Methods:We randomly assigned 279 patients with anterior STEMI who had undergone primary percutaneous coronary intervention(PCI)to receive,in a 1:1 ratio,low-dose rivaroxaban(2.5 mg twice daily for 30 days)and dual antiplatelet therapy(DAPT)or only DAPT.The primary efficacy outcome was the LVT formation within 30 days.Net clinical adverse events(NACE)were assessed at 30 days and 180 days,including all-cause mortality,LVT,systemic embolism,rehospitalization for cardiovascular events,and bleeding.LVT was ascertained through systematic screening echocardiograms followed by cardiac magnetic resonance imaging(if echocardiography was inconclusive).All endpoint events were adjudicated by an independent and blinded Clinical Endpoint Committee.Clinical trial no.Chi CTR1900026249.Results:Among patients with anterior STEMI who had undergone primary PCI,the addition of low-dose rivaroxaban to DAPT reduced LVT formation within 30 days,compared those with only DAPT(0.7% vs.8.6%;HR:0.08;95% CI: 0.01-0.62;P=0.015;Psuperiority < 0.001).NACE emerged the lower rates within 30 days in the rivaroxaban group versus the only DAPT group(6.5% vs.16.4%;HR: 0.37;95% CI: 0.17-0.80;P=0.011),and remained relatively low throughout the follow-up period(12.2% vs.25.0%;HR: 0.45;95% CI: 0.25-0.81;P=0.007).There were no significant differences in bleeding events within 30 days between the two groups(2.9% vs.1.4%;HR: 2.02;95% CI: 0.37-11.01;P=0.418).However,one case of intracranial hemorrhage(major bleeding)occurred in the rivaroxaban group.Conclusion:In patients with anterior STEMI following primary PCI,the short-duration addition of low-dose rivaroxaban(2.5 mg twice daily)to DAPT prevented LVT formation and reduced NACE compared with only DAPT.A larger multipleinstitution study is necessary to determine the generalizability.Part II.The Efficacy of Rivaroxaban in Patients with ST-segment Elevation Myocardial Infarction Combined with Left Ventricular Thrombus: a retrospective cohort studyObjective:In Part I,we investigated the effect of prophylactic rivaroxaban treatment on LVT formation in patients with anterior STEMI.In this part,we would focus on rivaroxaban treatment after the development of LVT in STEMI.Conventional triple anticoagulation [vitamin K antagonists(VKA)plus dual antiplatelet therapy(DAPT)]is the first-line therapy for left ventricular thrombus(LVT)after ST-segment elevation myocardial infarction(STEMI).In patients with LVT following STEMI,contemporary data of triple therapy with rivaroxaban are lacking.The aim of this part is to investigate the differences in clinical outcomes between the two triple therapy regimens(rivaroxaban vs.VKA)in the treatment of patients with STEMI combined with LVT.Methods:We conducted a retrospective cohort study involving 1,335 STEMI patients who underwent primary percutaneous coronary intervention(PCI).Among patients who developed LVT after STEMI,we observed differences in efficacy between rivaroxaban plus DAPT therapy and VKA plus DAPT.The time of LVT resolution was also evaluated,as well as net clinical adverse events,and rates of bleeding events.Ethical Approval no.2021081016.Results:In 1,335 patients with STEMI,a total of 77(5.7%)developed LVT over the follow up period(median 25.0 months).Low LVEF,large LVEDD,LV aneurysm,high hibrinogen,delayed revascularization,and the poor blood flow after revascularization are relevant factors for LVT.Of the patients diagnosed with LVT,31 patients were started on triple therapy with VKA,33 patients on triple therapy with rivaroxaban.There was a consistent similarity in LVT resolution with rivaroxaban application compared to VKA application during the follow-up period(78.8% vs.74.4%;Adjusted HR:1.70;95%CI: 0.90-3.22;P = 0.104).Triple therapy with rivaroxaban showed quicker resolution than with VKA(6months: P =0.049;12months: P = 0.044;18months: P = 0.045).Similar risks of ISTH bleeding were no significant difference between the 2 groups(6.1% vs.9.7%,Adjusted HR: 0.48;95%CI: 0.73-3.20;P =0.444).Fewer net adverse clinical events(NACE)were observed in the rivaroxaban group(24.2% vs.58.1%;Adjusted HR: 0.23;95%CI: 0.09-0.57;P = 0.001).Conclusion:In the observational study,triple therapy with rivaroxaban has similar and quicker LVT resolution in patients with LVT after STEMI,compared with triple therapy with VKA,and perhaps was associated with a better clinical benefit.Larger sample sizes and randomized controlled trials are needed to confirm this observation.Part III.The Preliminary Investigation of The Mechanism of Cardioprotective Effect in RivaroxabanObjective:In both Part I and Part II of this study,as well as in large randomized clinical trials,good clinical benefit has been observed with factor Xa(FXa)inhibitor rivaroxaban.FXa is an important transport pathway in the inflammatory and coagulation cascade,acting primarily through protease-activated receptors(PARs)and subsequently stimulating a variety of intracellular signaling,including the NF-κB and MAPK pathways,to induce the inflammatory cascade and fibrotic responses in a variety of pathological conditions.Meanwhile,the NF-κB pathway is an important myocardial inflammation-related signaling pathway,the activation of which contributes to ventricular remodeling after myocardial infarction.Based on the above background,this part aims to investigate whether the coagulation factor Xa inhibitor rivaroxaban can reduce the inflammatory response after myocardial infarction by down-regulating the activity of the NF-κB signaling pathway while improving ventricular remodeling and cardiac function.Methods:By ligating the anterior descending branch of the Wistar rat coronary artery to cause myocardial infarction,all surviving rats were randomly divided into three groups and given treatment on the first day after surgery: sham-operated group(anterior descending branch only without ligating the coronary artery),infarct control group and rivaroxaban group(rivaroxaban 3mg/kg/d by gavage).The three groups were counted 7 days after surgery.The surviving Wistar rats were anesthetized with isoflurane by inhalation and then assessed by cardiac ultrasound for changes in cardiac structure,including left ventricular ejection fraction(LVEF),left ventricular internal diameter shortening(LVFS),left ventricular end-diastolic internal diameter(LVIDd)and left ventricular end-systolic internal diameter(LVIDs),and then by hemodynamics at 7 days after surgery.Changes in cardiac function were assessed using hemodynamics,including left ventricular end-systolic pressure(LVESP),maximum rate of increase in intraventricular pressure during left ventricular systole(+d P/dt),and maximum rate of decrease in intraventricular pressure during left ventricular diastole(-d P/dt);blood was then rapidly collected from the abdominal aorta and heart specimens were stained with HE to observe changes in myocardial tissue structure.The expression of key inflammatory markers IL-6 and IL-1β in myocardial tissues of rats in each group was detected by immunohistochemistry, serum inflammation-related markers IL-6,IL-1β,and TNF-α in each group were detected by Elisa,and IL-6,IL-1β,and TNF-α in myocardial tissues,as well as total signaling pathway proteins NF-κB p65 and phosphorylated signaling pathway protein p-NF-κB p65 in myocardial tissue.In addition to this,to further validate the effect of rivaroxaban on the inflammatory response after myocardial infarction,we further used q RT-PCR to detect the expression of the relevant inflammatory marker genes IL-6,IL-1β,and TNF-α.Results:Compared with the sham group,the infarction control group showed significant left ventricular remodeling,enlargement of the left ventricular cavity,and thinning of the infarcted myocardium,while the ischemic area of necrosis was also evident in the rivaroxaban group,but the extent was smaller than that of the infarction control group,and the normal morphology of the left ventricle could be maintained.Cardiac echocardiographic and hemodynamic indices in the infarction control rats were significantly worse than in the sham-operated group(P<0.05),while the rivaroxaban group was significantly better than the infarction control group(P<0.05).HE staining and immunohistochemistry showed that compared with the sham-operated group,the myocardium of the infarct control group was disorganized,with obvious inflammatory cell infiltration,myocardial cell necrosis,and strong positive expression of IL-6 and IL-1β(++++),while the myocardial tissue of the rivaroxaban group showed a significant reduction of these pathological changes.Meanwhile,the results of Elisa,Western blot,and q RT-PCR showed that rivaroxaban effectively inhibited the expression of inflammatory factors IL-6,IL-1β,and TNF-α in serum and myocardial tissues of rats(P<0.05),and also down-regulated the protein expression of phosphorylated NF-κB p65(P<0.05).Conclusion:This part of the study showed that the coagulation factor Xa inhibitor rivaroxaban may have a protective effect against myocardial ischaemic injury in a rat model of myocardial infarction by inhibiting the inflammatory response after acute myocardial infarction,possibly through the inhibition of NF-κB signaling pathway activation. |
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