Bivalirudin Is Associated With Better Clinical Outcomes As Opposed To Unfractionated Heparin In Patients Undergoing Primary Percutaneous Coronary Intervention

Objectives:Globally coronary heart disease(CHD)is one of the most common causes of death with an estimated 7 million deaths per year.The majority of these deaths are due to acute myocardial infraction(AMI)so the burden of illness and mortality from AMI worldwide is high.The main treatment scheme for AMI with ST-segment elevation(STEMI)is thrombolysis and primary percutaneous coronary intervention(PCI).The aim of this study to evaluate the role of anti thrombotic therapy to prevent the adverse ischemic events during and after primary percutaneous coronary intervention(PCI)in patients with acute myocardial infarction(AMI).The clinical outcomes and efficacy of these antithrombotic agents should be weighed in against their relative risks of hemorrhagic complications.The main objective of this study was to compare the effect of bivalirudin with unfractionated heparin(UFH)anticoagulant therapies in patients with AMI undergoing primary PCI and to elucidate their clinical prognostic significance.Prevention of adverse ischemic events during and after primary percutaneous coronary intervention(PCI)in patients with acute myocardial infarction(AMI)is the essential role of antithrombotic therapy.Bivalirudin is a direct thrombin inhibitor(DTI)often expended for anticoagulation in the backdrop of invasive cardiology,predominantly percutaneous coronary intervention(PCI).Bivalirudin has an exclusive pharmacologic outline:opposing other advertised DTIs,it undergoes principal non-organ abolition(proteolysis),and has the shortest half-life(-25 min).Its likeness for thrombin is intermediate between that of lepirudin(highest)and argatroban(lowermost)—this helps explain why it interferes with functional clotting assays to an extent intermediate between that achieved by these two other DTIs.This effect is best known for the PT(INR)higher affinity for thrombin corresponds to lower molar DTI requirements to prolong the APTT;in turn,lower concentrations required for APTT prolongation(and,presumably,in-vivo effect)consequence in abridged PT(INR)perpetuation.Primary Percutaneous Coronary Intervention(PCI)is the crucial practice of PCI in individuals with AMI,mainly where there is advice of severe heart mutilation on the ECG.PCI is likewise expended in people after other forms of MI or unstable angina where there is a high risk of further events.PCI is an alternative to Coronary Artery Bypass Grafting(CABG)that bypasses stenosis arteries by grafting from away in the body.PCI is expended mainly to open a blocked coronary artery and reinstate arterial blood flow to heart tissue,deprived of requiring open-heart surgery.In patients through a limited or blocked coronary artery,PCI may be the greatest option to re-establish blood flow as well as avert angina,MI and death.Currently,PCI frequently compromises the supplement of stents,such by way of bare-metal stent,drug-eluting stents,and fully resorbable vascular scaffolds.In patients amongst AMI,PCI might be suitable;guidelines and greatest performs are continuously developing.In patients with severe blockages,such as ST-segment elevation myocardial infarction(STEMI),PCI can be critical to survival as it reduces deaths,MI and angina compared with medication.In most cardiac catheterization laboratories(cath lab)throughout the United States,Bivalirudin is used predominantly as a heparin substitute such as in patients has intolerance to heparin(e.g.history of HIT syndrome).Nevertheless,Bivalirudin clinical analyses have determined stable positive outcomes in patients with stable angina,unstable angina(UA),non-ST segment elevation myocardial infarction(NSTEMI),and ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention(PCI).This therapy also gained class I recommendation from the ACC/AHA updated guidelines for all of the above mentioned conditions.The extent of pre-treatment with various anti-thrombotic medications prior to arrival in the catheterization laboratory(Cath lab)of ACS patients is highly debated.Although pre-treatment with anti thrombotic drugs might appear to be of clear benefit in patients with STEMI,the problem is intricate.Pre treatment might prevent further clot formation and mediate in the body's own fibrinolysis with subsequent spontaneous reperfusion as well as decreased peri procedural complications.However patients might present as a suspected STEMI on the ECG but in fact have normal coronary vessels.Their symptoms might be due to other diagnoses like peri myocarditis,pulmonary embolism,aortic dissection,cardiac temponade,etc.these patients will thus have no beneficial effect of pre-treatment with anti thrombotic and might even take harm from it,especially if anti thrombotic surgery is required.The issue of pre-treatment is therefore complex and requires careful consideration.Bivalirudin is primarily used for its first Food And Drug Administration(FDA)permitted indication,namely anticoagulation during percutaneous trans luminal coronary angioplasty("balloon angioplasty"),the most common type of PCI.Bivalirudin is also indicated for PCI with provisional use of glycoprotein ?b/?a antagonist therapy,and for patients with,or at risk of,heparin-induced thrombocytopenia(HIT),or HIT with thrombosis syndrome(HITTS),undergoing PCI.The bivalirudin development program has used a "quadruple" end-point encompassing a "triple" efficacy endpoint plus major bleeding ? this tactic predicted the subsequent emphasis on strategies to improve clinical outcomes through bleeding reduction.Besides summarizing the key trials evaluating bivalirudin use for acute coronary syndrome(especially employing PCI),we evaluate also the studies of bivalirudin as anticoagulant on behalf of "on-" and "off-pump" cardiac surgery,including both HIT and non-HIT circumstances.Strategies to reduce bleeding have become an integral component of current PCI practice to decrease adverse outcomes.Bivalirudin,a direct thrombin inhibitor,has been demonstrated in multiple large-scale randomized trials to reduce major bleeding events after PCI among patients presenting with STEMI compared with UFH.However,bleeding reductions associated with bivalirudin therapy have occurred at the expense of increased rates of acute stent thrombosis.These trials have also varied in the proportion of use of glycoprotein Ilb/IIIa-inhibitors(GPI)in the UFH arm,ranging from infrequent to moderate to obligatory.Given the association of GPI therapy with increased bleeding and reduced ischemia,it is nit clear whether observed differences between bivalirudin and UFH may be,at least in part,secondary to greater use of GPI therapy with UFH.Bivalirudin is currently approved by the FDA as an anticoagulant to be used with aspirin in patients with unstable angina undergoing percutaneous trans luminal coronary angioplasty(PTCA)in elective non-emergent PCI.Bivalirudin doesn't alter restenosis rate post PCI.Anti-coagulation is obligatory throughout percutaneous coronary intervention(PCI)to counteract peri-procedural thrombotic impediments.Unfractionated heparin(UFH)and more newly the low molecular weight heparin(LMWH)is the most communal thrombin inhibitor(DTI)class of combinations has been estimated as an unconventional form of anti-coagulation at the time of PCI.Manifold clinical trials promptly reveal that bivalirudin is a safe and effectual anti coagulant for use in ACS and PCI.The diminution in bleeding complications competed with heparin-based approaches has been a coherent result across these studies.This has been validated deprived of loss of effectiveness in the preclusion of thrombotic complications.Reliant on the expenditure of bivalirudin,there may be cost-effective allowance generated through a reduction in the need for GP ?b/?a inhibitors and condensed rates of bleeding in both ACS and PCI.Materials and Methods:We performed a prospective,open label multicenter observational study in which patients with AMI undergoing primary PCI was randomized to bivalirudin or unfractionated heparin(UFH)alone.Between June 2013 and July 2015,639 patients were included in this prospective study.Patients were selected from the Shandong Provincial Hospital,Central Hospital of Tai'an,Dongying People's Hospital,Zibo City Central Hospital,and Qingzhou City People's Hospital.The choice of anti-thrombotic strategy was left to the discretion of the individual operator(s),which was based on their own clinical judgment and on patient's affordability.Patients were eligible for inclusion if they were aged between 18 and 80 years,presenting with AMI,including anterior,inferior or anterior + inferior MI within 12 hours after symptom onset or within 12 to 24 hours with ongoing chest pain,with ST-segment elevation or with a new left bundle branch block,and consequently underwent primary PCI with an approved device.Exclusion criteria included contraindication to any of the study medications,cardiogenic shock,uncontrolled hypertension(blood pressure>180/110 mmHg),prior or planned staged PCI within the preceding or following month,pregnancy or lactation,history of major surgery within one month,active or recent major bleeding or bleeding diathesis(gastrointestinal,genitourinary tract,prior intracranial bleeding or structural abnormality),known hemoglobin<10 g/dL,platelet count<100×109/L,renal insufficiency(CCR<30 mL/min),aminotransferase level>3×the upper limit of normal values and any condition resulting in unsuitable PCI or possible interference with study adherence,and patient unwilling or unable to provide written informed consent and unable to collect follow-up.Patient's criteria,which did not match the inclusion criteria,were excluded from the study group.Furthermore,patients without available data and follow-up were excluded.Consequently,after exclusion,a total of 459 eligible patients were enrolled in our study.The study protocol was approved by the Committee on the Ethics of Human Research at each clinical site,and complied with the principles of Helsinki's declaration.Written informed consents were obtained from all participants.Patients were assigned to 2 cohorts depending on the choice of anti-thrombotic therapy.Patients were administered the study medications prior to angiography in the catheterization laboratory.The rest group received bivalirudin(Shenzhen Salubris Pharmaceuticals,Guangdong,PRC)as a bolus of 0.75 mg/Kg followed by an infusion of 1.75 mg/Kg/h during the PCI procedure for a median of 3 hours.An additional bivalirudin bolus of 0.3 mg/Kg was administered when ACT was>225 seconds.The second group received unfractionated heparin mono therapy as an intravenous bolus of 100 IU/Kg according to the current guidelines with subsequent boluses targeted to an ACT>200 seconds.ACT was measured with the HemoTec assay,and 5 minutes after study drug boluses were administered.The anti-platelet regimen was administered according to the hospital's protocol.All patients received 300 mg of aspirin and an additional 300 mg of clopidogrel prior to the procedure.Other drugs such as Prasugrel and Ticagrelor were not administered due to their lack of availability in the concerned centers.Additional cardiovascular medications were administered according to the current guide-lines.Glycoprotein ?b/?a inhibitors(GPI)were not administered due to cost issues and increased bleeding risks.Selection of access sites,use of aspiration and stent type were in accordance with the local standards of care and at the discretion of the operator.The primary composite endpoints were major adverse cardiac or cerebral events(MACCE)defined by all-cause death,re-infarction,ischemia-driven target vessel revascularization,or stroke,or any bleeding,as defined by the Bleeding Academic Research Consortium(BA-RC)definition(grades 1-5)over a period of 30 days post-PCI,and clinical follow-up after sub-sequent hospitalization.Severe bleeding was defined as intracranial,intraocular or retroperitoneal hemorrhage,clinically overt signs of hemorrhage associated with a drop in hemoglobin of ?5 g/dL or a ?15%absolute decrease in hematocrit.Minor bleeding was defined as clinically overt bleeding,which did not meet criteria for major bleeding.Stent thrombosis was defined according to the Academic Research Consortium and was an additional safety end-point.Myocardial infarction was defined by new significant Q waves in 2 or more contiguous electrocardiographic leads or by the elevation in CK-MB isoform levels,resulting in a level at least 3 times higher than the upper limit of normal values.A blinded and independent clinical events committee made endpoint classifications.The analysis was carried out rather descriptively.Categorical variables were presented in number and percentage(%)and continuous variables were presented as mean ?standard deviation(SD).Applying continuity corrected chi-squared statistic of Fisher's exact test performed comparisons between the groups of categorical data.One way Analysis of Variance(ANOVA)was carried out for group mean comparison.Statistical significance was assumed at a value of P<0.05.All statistical analyses were performed with SPSS for Windows(version 20.0).Results:A total of 459 patients were enrolled in this study from four independent centers in Jinan,Shandong Province,PRC.Two hundred and twenty three patients(48.6%)were included in the bivalirudin arm and the remaining 236 patients(51.4%)received heparin mono therapy.Baseline characteristics and demographic data of enrolled patients are summarized.Mean age in the bivalirudin and heparin arm was 54.16 years and 56.19 years respectively.In both treatment groups,mean age was statistically similar.One hundred and thirty seven patients(61.43%)presenting with anterior MI,64 patients(28.70%)with inferior MI,and 22 patients(9.87%)with anterior + inferior MI were enrolled in the bivalirudin arm.One hundred and fifty six patients(66.10%)presenting with anterior MI,56 patients(23.73%)with inferior MI,and 24 patients(10.17%)with anterior + inferior MI,were enrolled in the heparin arm.Baseline characteristics as well as treatments and procedures were well matched between the groups.The incidence of procedural complications was low and similar between groups as demonstrated in Table 2,which indicates PCI results of enrolled patients assigned to the bivalirudin and heparin cohorts.Trans femoral access was used in all patients and PCI was performed with most patients receiving drug-eluting stents.Study medication adherence was high.Procedural success was found in 217 cases(97.31%)in the bivalirudin arm as opposed to 227 cases(96.19%)in the heparin mono therapy arm(P=0.4988).Failure was found in 6(2.69)and 7 cases(2.97)in the bivalirudin and heparin arm,respectively(P=0.859).However,both these variations in results were not statistically significant Death cases(0 vs.0.85%)and no-flow(4%vs.9%)cases were similar in both arms with a slightly higher percentage of slow cases in the heparin arm(7 vs.16%)but did not reach statistical significance(P= 0.5036,0.192,and 0.074 respectively).The incidence of stroke(hemorrhagic)and stent thrombosis were also similar in both bivalirudin and heparin cohorts(0.9%vs.2.97%and 0.9%vs.1.27%,respectively).Statistical differences were also insignificant(P=0.2072 and P>1.00,respectively).However,there was a significant difference in the all-cause bleeding cases in the bivalirudin arm as opposed to the heparin arm(5.38 vs.13.98%;relative risk[RR]for bivalirudin vs.heparin,0.3024;95%CI=0.06347-1.441;P=0.002).This difference could be attributed to the post-PCI infusion of bivalirudin,which was administered to all patients in the bivalirudin arm.The 30-day clinical follow-up of all patients grouped into bivalirudin and heparin arms.As shown in Figure 1A,9 patients(4.04%)treated with bivalirudin while 25(10.59%)treated with heparin only,experienced a statistical significant difference in all bleeding events(including access and non-access sites)at the primary 30-day endpoint(relative risk[RR]=0.3810;95%CI=0.1818-0.7983),P=0.0073).The ratesof major adverse cardiac or cerebral events(4.48%vs.9.32%;RR=0.4329;95%CI=0.2037-0.9200,P=0.0-241)and its individual components were also statistically significant between the 2 groups(Figure 1B).In addition,there was a statistically significant difference in the rates of severe bleeding in the bivalirudin and heparin cohorts(0.45 vs.5.51%;RR=0.0814;95%CI=0.01073-0.6175,P=0.0016)after 30 days(Figure 1C).Among patients receiving stents,no statistically significant differences were found in the 30-day rates of stent thrombosis(0.45 vs.0.85,P=0.9617),in patients treated with bivalirudin or heparin alone.There were also no statistically significant differences in the cardiac and all-cause deaths at 30 days in the bivalirudin and heparin arms(0.9%vs.1.27%,P>1;and 0.45 vs.2.12%,P>1,respectively).Conclusion:In ACS patients delay greater than 24 hours in time to PCI may be associated with increased ischemia and bleeding compared to rapid intervention.Bleeding complications are not increased when using bivalirudin alone.Compared to unfractionated heparin(UFH)with or without GP ?b/?a inhibitor,bivalirudin mono therapy signify reduces major bleeding while providing similar ischemic protection regardless of time to PCI.The reduction in mortality with bivalirudin as compared with unfractionated heparin plus glycolin ?b/?a inhibitors in the present trial may be attributed to the prevention of iatrogenic hemorrhagec complications.Among patients in whome a stent was successfully implanted,assignment to bivalirudin,as compared with heparin plus glycolin ?b/?a inhibitors,resulted in 17 more episodes of stent thrombosiss within the first 24 hours,representing a significant increaseThere were several limitations to this study.First,the study population was small and it was an open-label design,thereby introducing the possibility of a potential bias.Secondly,due to the unavailability of a screening log,the generalization of the study findings cannot be accessed directly.Third,bivalirudin used in the present study was manufactured by a different pharmaceutical company(Shenzhen Salubris Pharmaceuticals)as compared to the previous trials but it has identical molecular weight,similar anti-thrombin potency and half-life as the originator product.Fourth,in the heparin mono therapy group,we used the recommended guideline,namely a heparin dose of 100 IU/Kg,which is higher than the dose,used in previous trials but is consistent with the recent BRIGHT trial,Other notable limitations include the unavailability of Prasugrel and Ticagrelor in the institutions under the present trial,the omission of Glycoprotein ?b/?a inhibitors(GPI)due to cost issues and patient non-compliance,and the general incorporation of all BARC bleeding points into the primary end-point.These limitations,however,did not affect the overall study design nor did they affect the outcomes of the study.Bivalirudin was associated with significant reductions in all-cause bleeding,severe bleeding,and major adverse coronary and cerebral events following prolonged hospitalization(30 days)which further cements its role as a novel and potent anti-thrombin drug,greatly superior to heparin.These desired effects could be attributed to the 3-hour median post PCI bivalirudin infusion.The study also demonstrated fewer incidences of stent thrombosis as compared to heparin mono therapy contrary to the previous trials,which warrants a more extensive study to evaluate the clinical efficacy of the drug and it's undermining adverse effects.Bivalirudin is a very promising direct thrombin inhibitor with favorable pharmacokinetics and pharmacodynamics.It has been shown to be superior to UFH in the setting of PCI and could be used as a substitute for heparin and GP ?b/?a inhibitors in non-emergent interventions and in and in patients with HIT.Also,bivalirudin is safe and effective in PPI,but randomized trials are lacking.The use of bivalirudin in high-risk interventions such as emergent acute coronary syndromes or chronic limb ischemia appears promising but more data are needed to demonstrate its safety and cost-effectiveness.