Comparison Of The Different Effects Of Ticagrelor And Clopidogrel On The Inflammatory Mediators And Function Of Endothelial Cells In Patients With STEMI Undergoing PCI

Background:Acute myocardial infarction(AMI)is an acute necrosis of some myocardium due to severe and persistent reduction or interruption of myocardial perfusion,and is a serious common disease,with extremely high disability and death rates.The fundamental pathophysiological mechanism is rupture of vulnerable plaque with thin fibrous cap and a large amount of inflammation,surface erosion of plaque,intraplaque hemorrhage,dysfun-ction of coronary endothelial cells,exposure of tissue factor and collagen,which leading to the activating of platelet and coagulation mechanism,thrombosis with or without coronary spasm,eventually leading to partial or total coronary artery occlusion.Endothelial dysfunction is thought to be a pivotal event in the development of atherosclerosis.It is believed that inflammation is closely related to the progression and instability of atherosclerotic plaques.Therefore,the therapeutic principles of AMI is reperfusion therapy as soon as possible,including on the premise of opening coronary artery,anti-platelet aggregation,anti-coagulation,regulation of inflammatory reaction in related position of lesion and improvement of the function of coronary endothelial cells.It is well known that platelets play an important role in thrombosis.In addition,it is also a source of inflammatory mediators,and platelet activation triggered by inflammation is an important part of atheros-clerosis.Whether plaque rupture,surface erosion,plaque hemorrhage or regulation of thrombosis,inflammatory factors play an important role.After stent implantation,significant inflammatory responses were also observed,so anti-inflammatory therapy should also be considered in STEMI therapy.As an increasing number of evidences implicated the close relation between inflammation and thrombosis,artery endothelial dysfunction,effective inhibition of platelet function can also contribute to anti-inflammatory and improvement of vascular endothelial function.Aspirin and clopidogrel,as a dual antiplatelet therapy,have been recommended by relevant guidelines for first-line treatment of AMI.Considering only that the united antiplatelet therapy,the anti coagu-lation effect is the onefold effect is so simplistic.At present,experiments have confirmed that antiplatelet agents,aspirin and clopidogrel have direct or indirect anti-inflammatory effects.Liverani,et al.found that the P2Y12 ADP receptor antagonist also had some anti-inflammation effects,the antiplatelet effect of clopidogrel was associated with its anti-inflammatory effects,its combination with aspirin could protect vascular endothelial function,reduced the expression of inflammatory cytokines,such as c-reactive protein,P-selection,CD40 ligand,etc,reduced the level of inflammatory factors in patients with ischemic vascular disease,especially patients with acute coronary syndromes(ACS)undergoing percutaneous coronary interention(PCI).However,with the progresses of research in AMI and anti-platelet therapy,it is found that there are many limitations of clopidogrel,such as great variation in populations,slow effect,irrever-sibility of antiplatelet action and clopidogrel resistance(CR).Then,the result of antiplatelet effect in the standard combination therapy is greatly different,especially for AMI patients receiving PCI,the key question is major adverse cardiac events(MACEs)after operation.The focus of platelet activation and aggregation in the postoperative stent thrombosis of AMI and.PCI is that the activation of G protein coupled receptor P2Y12 on platelet surface is the key pathway.Therefore,dual antiplatelet therapy(DAPT),platelet P2Y12 receptor antagonist combined with aspirin is still the cornerstone for the prevention and treatment of stent thrombosis after STEMI and PCI.PLATO trial showed that compared with clopidogrel,ticagrelor could significantly reduce the risk of cardio-vascular events in patients with ACS,reduces cardiovascular death and total mortality.The anti-platelet aggregation is stronger and faster,thus reducing the incidence of acute stent thrombosis.The overall risk of severe bleeding did not increase.In recent years,because of a good anti_platelet aggregation effect,the role of clopidogrel in STEMI therapy has been confirmed by various guidelines,especially the 2017ESC guide,in which it becomes the first choice for the DAPT in the STEMI.Does ticagrelor,like aspirin and clopidogrel,have the same effect on antiplatelet,anti-inflammatory and improvement of endothelial cell function,in patients with STEMI treated with PCI?There is less or contradictory conclusions in recent research.Based on previous research results,P-selection,C-reactive protein,CD40 ligand were selected in this study,and the anti-inflammatory effect of ticagrelor and clopidogrel was examined,comparing the levels of inflammatory levels between groups of the patients in preoperation,intraoperation and postoperation.The level of NO,vWF,sICAM-1,%FMD and%NTG were tested,comparing the effects of ticagrelor and clopidogrel on endothelial function.The study included two parts.Part1Objective:To investigate the effect of ticagrelor on the inflammatory factors in patients with STEMI undergoing PCI in early stage.Methods:This study is a mlti-center,randomized,open trial.347 patients with STEMI were randomly divided into two groups,155 patients in ticagrelor group(T group)and 192 patients in clopidogrel group(L group).All the patients were treated with aspirin(loading dose 300mg each person-time;then 100mg qd).The patients in the ticagrelor group took ticagrelor(loading dose 180mg each person-time;then 90mg bid),while the patients in the clopidogrel group took clopidogrel(loading dose 600mg each person-time;then 75mg qd).According to the results of coronary angiography and PTCA,the subgroups with heavy thrombus load,three coronary arteries lesions and diffuse lesion were selected in each group.There were 86 patients with heavy IRA thrombus load and/or diffuse lesion(Th group)in ticagrelor group,and 91 patients(Lh group)in clopidogrel group.Between the two groups and subgroups,the concentration of hr-CRP,CD40L and P-selection in venous blood and coronary artery blood were compared before PCI(before taking the medicine),lh,24h,1w,and 4w after taking the medicine.All the sample were tested in the central laboratory Jinan Central Hospital.The data obtained were statistically analyzed by using SPSS 21.0 software.Continuous variables were expressed by x ±s and compared using independent-samples T-test;Categorical variables were expressed by percentages and compared using χ2 test or Fisher’s exact test;Paired-Samples T-Test were used to compare the numerical application of the two groups and subgroups at different time.P<0.05 was considered to be statistically significant.Results:1.Baseline clinical data including age,sex,blood pressure,heart rate,BMI,CR,percentage of neutrophils in white blood cells,left ventricular ejection fraction,hypertension history,angina pectoris history,smoking history,diabetes history,uric acid,insulin therapy history,stroke,family history of coronary heart disease and IRA,drug combination after PCI had no statistical significance between the two groups and subgroups(P>0.05).2.Comparison of PCI data in two groups and subgroups:Of 347 patients who underwent PCI,335(96.5%)underwent radial artery puncture,and 12(3.5%)underwent femoral artery puncture.There were 753 diseased vessels,473 stents,including single coronary artery desease 67 cases(19.3%),double artery desease 154 cases(44.4%),and three-artery desease 126 cases(36.3%).Of the infarcted related artery(IRA),anterior descending branch(LAD)163 cases(46.97%),LCX 61 cases(17.58%),right coronary artery(RCA)115 cases(33.14%),and 8 cases(2.31%)of the left main coronarylesion.There were no statistically significant difference between T group,L group and h-subgroups,in the number of patients in the group,in the number of lesion vessels,in the number of stent placement,and in the length of the stent(P>0.05,table 1).3.The levels of inflammatory factors in the two groups and subgroups were similar atbaseline(P>0.05,table 2).4.The character of the intracoronary inflammatory factors:The levels of CD40L and P-selectin were significantly higher than those of venous blood(1 h)at the same time(P<0.01,table 2).and there was no significant difference in the levels of three inflammatory factors between the two groups and the two subgroups.However,there was no significant difference between the venous blood levels of hs-CRP and that of the same period.5.24 hours after operation,the three inflammatory factors were all significantly increased,and there was no significant difference between the two groups and the two subgroups(P>0.05,table 2).6.On the 7th day after operation,there was no significant difference in the level of inflammatory factors between T group and L group,and at the highest level of P-selectin,CRP and CD40L.But there was no significant difference in CD40 level between subgroup Th and Lh group(P<0.05)and the CD40L level of Th group was lower than that of Lh group(P<0.05).7.28 days after PCI,the hs-CRP and P-selectin level have fallen significantly compared with that from 7 days after PCI(P<0.01),CD40L keep the high level,there was no significant difference between T and L groups(P>0.05),while CD40L were beginning to decline obviously in the group Th compared with that of group Lh(P>0.05).8.Compared with that of 7th day time point,the variation amplitude of inflammatory factors were all similar except the CD40L level in the subgroups that they have less increasion in group Th(P<0.05).9.The concentration of CD40L was increased persistently in baseline,intraoperative,24h and 7 days after PCI.There were significant differences between groups(P<0.01).Compared with the concentration level of groups Lh and L at 7th day time point,there were insignificant drop of CD40L in groups Th and T at 28th day time point(P<0.05).10.The concentration peak of P-selectin was reached 24 hours after PCI,then gradually decreased,and there was a significant decline in the 28th and 7th day time point(P<0.01).There was no difference of decent degree between the two groups and subgroups(P>0.05).11.The changes of hs-CRP were relatively large,and the postoperative concentration level gradually increased,and reached the peak level at 7th day,then showed a significant decrease at 28th day timepoint,and was significantly lower than the preoperative level(P<0.01).Then the decrease of T group was more significant than that of L group,Th group than thar of Lh group(0.01<P<0.05).12.There was no significant difference in data consistency and sensitivity test in different test centers(P>0.05).13.The follow-up results of adverse drug reactions and MACEs:During a follow-up of 28 days,2 patients in L group had MACEs:One case of cardiac death and one case of stroke.One patient in groupL(0.52%)had subcutaneous ecchymosis,and 5 patients in group T had slight bleeding,2 patients had slight dyspnea(1.32%),no minor bleeding,no fatal bleeding and bleeding in need of treatment.So patients in group T had more non-MACEs events than group L(P=0.025).Conclusions:1.Both ticagrelor and clopidogrel had dual effects of anti-platel-et aggregation and anti-inflammatory in STEMI patients undergoing PCI.2.Compared with clopidogrel,ticagrelor had a better effect on CD40L and CRP than clopidogrel after 1 week,but there was no significant difference in the effect on P-selectin.3.There is insufficient evidence to determine overall that ticagrelor has a better anti-inflammatory effect than clopidogrel.4.Ticagrelor was safe in STEMI-PCI patients in the early phase.Part 2Objective:To investigate the effects of ticagrelor on the function of vascular endothelial cells in patients with STEMI treated with PCI in the early stage.Methods:155 patients in ticagrelor group(group T)and 192 patients in clopidogrel group(group L)were enrolled in this study.The peripheral venous blood of the selected patients was extracted above 3ml(cubital vein)before taking the medicine and 10d,28d after PCI,and placed in sodium citrate anticoagulant tubes,shaked up,laid aside for 30 minutes.Then there were 4000r/min centrifuged for 6min×2 times.Plasma sample were got from supernatant,and stored in-80℃ refrigerator.They were to be tested uniformly.The plasma concentration of nitric oxide(NO),von Willebrand disease factor(vWF),soluble intercellular adhesion molecule(sICAM-1)were observed.The baseline patient’s%FMD were collected before PCI.The stable condition was The brachial artery endothelium-dependent vasodilations were detected in the morning at 10 d and 28 d after PCI when patients were being in a stable condition.All of the specimens were detected in the same laboratory.All the data were statistically analyzed by using SPSS 21.0 software.Continuous variables were expressed by means and standard deviation and compared using independent two-sample T-test;Categorical variables were expressed by percentages and compared using Fisher’s exact test or χ2 test;Paired-Samples T-Testwere used to compare the continous variables of the same group at different timepiont.P<0.05 was considered to be statistically significant.Results:1.Baseline clinical data including blood fat,blood sugar,BNP,LVEF,medication situation,BAD,maximum blood flow velocity of brachial artery，left ventricular ejection fraction,Other laboratory data before and after PCI had no statistical significance between the two groups(P>0.05).2.The levels of NO,vWF,sICAM1 and%FDM were similar at baseline(P>0.05).Considering the effects of nitroglycerin and other drugs and some Patients were with hypotension,%NTG were not recorded at baseline.3.The concentration of NO decreased at 10th d compared with baseline(P<0.05).while increased at 28th d(P<0.01).There was no significant difference between the two groups at 10th d(P=0.65).The NO in group T increased obviously,there was a significant difference between the two groups at 28th d.4.The concentration of vWF increased signally at 10th d and more dramatically at 28th d compared with baseline data(P<0.01).Compared with clopidogrel group,there was insignificant difference between group T and group L in the degree of decline of vWF at 10th d,but significant decline at group T at 28th d(P<0.05).5.The concentration of sICAM-1 had a significant decrease in group T,while it was not obvious in group L at 10th d.By the 28th day,the decrease in group T was more significant than that in group L(P<0.01).The decrease in group L was later,but it was significantly decreased at 28th d.On the 28th day,there was a more significant decrease in group T than group L(P<0.05),and almost the same at other time point.6.The level of endothelium-dependent vasodilatation function of brachial arteries(%FMD)improved significantly in both groups at 10th d compared with baseline data(P<0.01),and there was no significantly difference between the two groups.There was a further improvement of%FMD in both groups at 28th d,and%FMD showed a higher level in group T than that in group L.Considering that a large number of vasoactive drugs have been used in emergency patients,the baseline%NTG is not reliable,so we give it up at baseline.There was no significant difference between the two groups at 10-day follow-up.The results showed that%NTG in group T was signifi-cantly higher than that in group L at 28-day follow-up.Conclusions:1.Ticagrelor can improve endothelium-dependent diastolic function of peripheral blood vessels.2.Ticagrelor may have protective effect on coronary vascular endothe-lial function in STEMI patients treated with PCI,which can effectively promote early recovery of cardiovascular function.Total Conclusions:1.Both ticagrelor and clopidogrel had the dual effects of anti-platelet aggregation and anti-inflammatory in STEMI-PCI patients.2.Compared with clopidogrel,ticagrelor had a better effect on CD40L and CRP than clopidogrel after 1 week,but there was no significant difference in the effect on P-selectin.3.There is insufficient evidence to determine overall that ticagrelor has a better anti-inflammatory effect than clopidogrel.4.Ticagrelor was safe in STEMI-PCI patients in the early stage5.Ticagrelor can improve endothelium-dependent diastolic function of peripheral blood vessels.6.Ticagrelor may have protective effect on coronary vascular endothelial function in STEMI patients treated with PCI,which can effectively promote early recovery of cardiovascular function.