| Background:Acute ST-segment Elevation Myocardial Infarction is one of the most commonly-seen urgent critical illnesses that threaten not only the well-being of human life,but also patients' quality of life.The most effective treatment option for patients is undergoing primary percutaneous coronary intervention(PPCI)as soon as possible.However,No-reflow(NR)occurs in some patients after PPCI,resulting reperfusion disorder of the ischemic myocardium,which severely affects the short-term and long-term prognosis of AMI patients.NR is a multifactorial phenomenon.The major mechanism include distal thromboembolism post-dilation or after stenting of the target vessel,myocardial and endothelial edema,capillary occlusion,and ischemia-reperfusion injury and so forth,where the critical prophylaxis and treatment is to prevent thrombosis of coronary microcirculation and alleviate thrombotic burden of target vessel.The hypothesis of this study is that intra-coronary injection of bivalirudin in the context of intravenous injection with loading dose and subsequent infusion of bivalirudin for anticoagulation treatment during PPCI might help alleviate the thrombotic burden of focal coronary artery and improve coronary microcirculation,thereby preventing NR.We try to establish effective reperfusion animal model of STEMI,to explore the efficacy and safety of this novel treatment modality,and attempted preliminary study on human subjects.Aim:To establish STEMI reperfusion animal model,and explore the efficacy and safety of intravenous and intracoronary application of bivalirudin on STEMI patients during PPCI to coronary flow restoration.Methods:Part 1:To establish STEMI reperfusion animal model and preliminarily explore the efficacy and safety of intracoronary infusion of bivalirudin and other drugs to coronary flow restoration with this model.On the first stage,we explore the dosing of bivalirudin peri-operational anticoagulation(with 4 male Bama minipig,bodyweight 25-35 kg)to be 0.75mg/kg(intravenous loading dose injection)and 3.0mg/kg/h(intravenous infusion).Secondly,we explore the timing of balloon dilation of mid-distal left anterior descending coronary artery(ostial second diagonal branch)with 12 minipigs.On the second stage,10 minpigs were 1:1 randomized into the experimental group(intracoronary bivalirudin injection twice,0.75mg/kg)and control group(intracoronary saline injection twice)to compare coronary flow restoration of infarct artery,infarcted myocardial area,and elevation of myocardial enzymes.On the third stage,bivalirudin(0.75mg/kg)was combined with Pro-urokinase(0.4mg/kg)via intracoronary injection(with 3 minipigs),which was compared with intracoronary bivalirudin injection(0.75mg/kg,with 5 minipigs),to assess the difference in flow restoration of coronary reperfusion.Part 2:To explore the efficacy and safety of intracoronary bivalirudin infusion with certain dosage to coronary flow restoration on STEMI patients undergoing PPCI with standard intravenous bivalirudin application: a single-centered,prospective,open-labeled,randomized exploratory clinical trial.Stage 1: 84 STEMI patients undergoing PPCI in the Department of Cardiology of the General Hospital of Northern Theater Command were included in this study.All patients received standard bivalirudin anticoagulation(0.75mg/kg intravenous bolus injection,1.75mg/kg intravenous infusion until 3-4 hours post-PPCI)and were randomized as experimental group(44 patients)and control group(40 patients).Intracoronary inject bivalirudin(0.375mg/kg,half of intravenous bolus dose)or saline(5ml)as blood flow of infarct-related artery restores(TIMI flow?2 grade)and observe primary endpoint: coronary flow restoration(corrected TIMI frame counted-CTFC and TIMI flow)immediately after stenting and post-PPCI,complete regression(ST segment regresses ?70% of maximum amplitude of elevation)ratio of ST-segment of electrocardiography 90 minutes post-PPCI.The secondary endpoint include intraprocedural thrombotic events(IPTE),ratio of intracoronary salvage injection administration of bivalirudin,tirofiban and sodium nitroprusside after stenting,net clinical adverse events(NACE,including all-cause mortality,recurrent myocardial infarction,target vessel revascularization,stroke,stent thrombosis,and BARC-defined bleeding events)30 days post-PPCI.Stage 2: 128 STEMI patient undergoing PPCI were included with the same inclusion/exclusion criteria,and were randomized into 3 groups: bivalirudin group(intracoronary injection,0.75mg/kg,46 patients),tirofiban group(intracoronary injection,500 ug/10 ml,42 patients),and control group(intracoronary injection of 10 ml saline)to observe primary and secondary endpoints.Results:Part 1: Acute myocardial infarction was well generated in areas where blood supply was blocked via balloon dilation of mid-distal left anterior descending coronary artery(ostial second diagonal branch)of Bama minipig for 40 minutes on stage one,yet with a low rate of focal coronary thrombosis.On stage 2,we extended the balloon dilation to 60 minutes and successfully established acute STEMI reperfusion animal model.In the context of intravenous anticoagulation with bivalirudin,intracoronary bivalirudin injection twice(0.75mg/kg)remarkably improved blood perfusion of infarct-related artery(CTFC)and significantly alleviate severity of myocardial infarction(ratio of infarcted myocardial area,and values of creatine kinase)as compared with control animals.Intracoronary injection of bivalirudin(0.75mg/kg)with recombinant human urokinase(0.4mg/kg)had no effective on coronary flow restoration for this animal model.Intracoronary bivalirudin injection was safe in the context of intravenous bivalirudin infusion as no bleeding event occurred with all animals.Part 2: stage 1 results showed in the context of intravenous bolus injection and infusion of bivalirudin with regular standard dosages during PPCI for STEMI patients,when blood flow of infarct-related artery restores(TIMI flow?grade 2),no obvious difference was observed in terms of coronary flow restoration immediately after stenting and post-PPCI,complete regression ratio of ST-segment of electrocardiography 90 minutes post-PPCI,IPTE,NACE at 30 days,and ratio of intracoronary administration of tirofiban and/or sodium nitroprusside during PPCI,between intracoronary bivalirudin injection(0.375mg/kg,half of intravenous bolus dose)group and control group.Stage 2 results showed that for STEMI patients,with abovementioned anticoagulation during PPCI,intracoronary injection of bivalirudin with the same dosage as intravenous bolus injection(0.75mg/kg),or intracoronary injection of tirofiban 500ug(10ml)as blood flow of infarct-related artery restores(TIMI flow?grade 2)significantly reduced no-reflow(CTFC?40 or TIMI flow ? grade 2)of target vessel immediately after stenting and post-PPCI.Yet no difference was observe between three groups in terms of complete regression ratio of ST-segment of electrocardiography 90 minutes post-PPCI,IPTE,and NACE at 30 days.Although we observed ACT value had transient and remarkable elevation during PPCI in bivalirudin group,it resumed and was comparable with the other 2 groups after PPCI and no bleeding event was observed.Conclusion:For the first time,this serial exploratory study established experimental acute STEMI reperfusion swine model in the context of bivalirudin anticoagulation with high successful modeling rate,which is expected to be further applied in the upcoming relevant studies.This preliminary study also demonstrated that combined intravenous and intracoronary bivalirudin administration was safe and plays a preventive role in no-reflow of infarct-related artery after stenting. |
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