Effects Of Thrombolysis Followed By Early Percutaneous Coronary Intervention On Myocardial Perfusion In Patients With ST-segment Elevation Myocardial Infarction And The Protective Effects Of Anisodamine On The Myocardial Perfusion And Renal Function

ST-segment elevation myocardial infarction (STEMI) is one of the most severe types of heart attack which usually occurs when thrombus forms on a ruptured atheromatous plaque and occludes an epicardial coronary artery. Approximately17million deaths related to the coronary artery occur each year in the world, and half of them due to STEMI. In recent years, the prevalence of STEMI is growing rapidly in China, with the high mortality in the early stage.Early and effective reperfusion therapy is the most important treatment for STEMI patients. However, only3%of STEMI patients received primary percutaneous coronary intervention (PCI) within12hours of symptom onset, which indicated that effective reperfusion was not achieved in the majority of STEMI patients in China. In order to reduce the time delay and improve the success of reperfution, an advanced pharmacoinvasive therapy which combined medical treatment with PCI may be the direction of treatment for STEMI in the future. However, the effects of myocardial perfusion, bleeding complications and outcoms of early PCI following thrombolysis should be further studied.Anisodamine (6-[s]hydroxyhyoscyamine), a belladonna alkaloid derived from the Chinese medicinal herb Scopalia tangutica Maxim of the Solanaceae family that is indigenous to Tibet, is a blocker of M-choline receptors and has the effect of improving the microcirculation and increasing tolerance to ischemia in patients with microcirculatory disorders. Several latest large clinical trials suggested that platelet GP Ⅱb/Ⅲa inhibitor tirofiban could significantly improve reperfusion of infarct area and clinical outcomes of STEMI patients. Our precious studies have shown that intracoronary administration of anisodamine and tiroftban can further improve the coronary flow in STEMI patients underwent primary PCI. So far, the effect of intracoronary administration of anisodamine and tirofiban on myocardial perfusion in STEMI patients undergoing early PCI following thrombolysis and the interaction between them have not been carried out.Based on our previous work, this study was designed to evaluate the effect of early PCI following thrombolysis via transradial artery approach on myocardial perfusion, and the preventive effect of anisadamine on contrast induced nephropathy. The possible mechanisms were also probed.The detailed methods and results of our study are as follows:Part ⅠSafety and Efficacy of Thrombolysis followed by Early Percutaneous Coronary Intervention via Transradial Artery Approach in Patients with ST-segment Elevation Myocardial InfarctionObjective:This study was to compare coronary flow, myocardial perfusion, left ventricular function and major adverse cardiac events (MACE) between thrombolysis followed by early percutaneous coronary intervention (PCI) via transradial artery approach and primary PCI, and to investigate the safety and efficacy of thrombolysis followed by early PCI via transradial artery approach in patients with ST-segment elevation myocardial infarction (STEMI).Methods:From September2009to March2010, all consecutive STEMI patients within12hours from symptom onset or thrombolysis in the Department of Cardiology of the Second Hospital of Hebei Medical University were enrolled. All eligible STEMI patients were divided into two groups according to patients received thrombolysis or not:early PCI group (E-PCI group, patients received thrombolytic agents in non-PCI capable hospital and immediately transferred to receive early PCI) and primary PCI group (P-PCI group, patients received primary PCI). Coronary angiography (CAG) and PCI were performed immediately after admission via transradial artery approach for patients in both groups with standard technique. According to the results of angiography, PCI was performed unless the blood flow of IRA achieved TIMI flow grade3without significant stenosis. The other medications were administered to the patients (including aspirin, clopidogrel, diuretics, isotropic agents, intravenous vasodilator, lipid-lowering, beta-blockade, and angiotensin of converting enzyme inhibitors) according to current best practice. Thrombus score, TIMI flow grade (TFG) of IRA before and after PCI, corrected TIMI frame count (CTFC), TIMI myocardial perfusion grade (TMPG) post PCI were analyzed. Bleeding complications was also observed and evaluated. All patients were followed up for6months to assess major adverse cardiac events (MACE). The primary end point was myocardial perfusion post PCI assessed by TFG, CTFC and TMPG, and the second end points were bleeding complications during hospital and30-day MACE. SPSS17.0for Windows (SPSS Inc., Chicago, Illinois) was used for statistical analysis. Values of P<0.05were considered statistically significant.Results:A total of161cases were enrolled, with53cases in E-PCI group and108cases in P-PCI group. The patients in E-PCI group were younger than those in P-PCI group (51.36±12.24vs.57.31±9.87, P=0.003). The other baseline clinical characteristics such as gender distribution, baseline levels of serum BNP, SCr and Hb, and the medication therapies were similar between the two groups (all P>0.05). The mean time from symptom onset to thrombolysis was3.62±1.85h in E-PCI group, and the time from thrombolysis to PCI was5.13±3.03h. Compared to P-PCI group, the mean time from onset to PCI was longer in E-PCI group (8.75±2.86vs.6.03±3.19h, P<0.001). There were no differences in door to balloon time and IRA distribution between the two groups. Of the53patients treated with thrombolysis,51patients underwent early PCI when transferred to our hospital except2patients who only underwent CAG. In the P-PCI group,106patients underwent primary PCI, while2patients underwent CAG. Before PCI procedure, the thrombus score of IRA in E-PCI group was lower, and the percentage of TIMI3flow was higher (both P<0.05) compared to those in P-PCI group. TFG of IRA after PCI was similar, and there was no significant difference in the volume of contrast medium (P>0.05). However, CTFC of IRA post PCI in E-PCI group was lower than that in P-PCI group (28.12±5.06vs.30.89±8.74, P<0.05), and rate of TMPG3in E-PCI group was higher than that in P-PCI group (82.8%vs.68.0%, P<0.05). All of the implanted stents were drug-eluting stents. No differences were found in the stent implantations between the two groups (all P>0.05). There was a trend toward lower in the peak value of serum CK-MB in E-PCI group. No significant differences were found in the incidence of bleeding complications and hospital stay between the two groups. There was a trend of better left ventricular function7days after PCI in E-PCI group than that in P-PCI group. After6-month follow-up, the left ventricular function was improved in both the two groups (all P<0.05), and there was still a better trend in E-PCI group. Overall, there was no significant difference in6-month MACE between the two groups (P=0.977).Conclusion:1. The myocardial perfusion was better in patients undergoing thrombolysis followed by early PCI, and there was a trend of improving left ventricular function in patients underwent thrombolysis followed by early PCI, without increases of bleeding complications and incidence of MACE.2. It is safe and efficacious for STEMI patients to receive thrombolysis followed by early PCI via transradial artery approach. Part IIPrediction of hemodynamic parameters on myocardial perfusion in patients undergoing early percutaneous coronary intervention following thrombolysis and the myocardial protective effects of anisodamineObjectives:This study was designed to investigate the relation between hemodynamic states before PCI and myocardial perfusion after early percutaneous coronary intervention (PCI) following thrombolysis, and to observe the predictive effects of anisodamine on myocardial perfusion in patients with ST-segment elevation myocardial infarction (STEMI) undergoing early PCI following thrombolysis.Methods:This study was performed as a two-phase study.Phase1represented a retrospective analysis of the consecutive STEMI patients undergoing early PCI following thrombolysis who were admitted to the second hospital of Hebei medical university from June2007to June2009. According to the TIMI myocardial perfusion grading (TMPG) after PCI, all the eligible patients were divided into poor perfusion group (TMPG≤2) and normal perfusion group (TMPG=3). The systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate before PCI were recorded. The TIMI flow grade (TFG), corrected TIMI frame (CTFC) and TMPG, as well as thrombosis score were compared between the two groups. The peak value of CK-MB was monitored and evaluated as infarction area. Echocardiographic examination was performed at discharge by a cardiologist blinded to the randomization results. Left ventricular ejection fraction (LVEF) was determined from apical2and4chambers views by Simpson’s biplane formula. Medications were also recorded in a database. Univariate logistic regression was used to analyze the baseline characteristics, angiograph characteristics and hemodynamic states before PCI. The TMPG was used as dependent factor, and multivariate logistic was performed to analyze the independent variants which were selected by univariate logistic regressions. The odds ratios (ORs) and their corresponding95%confidence intervals (CIs) were provided. The logistic regression equation was established according to the result of multivariate logistic regression to predict the risk of incomplete perfusion (TMPG≤2) after PCI. The receiver operating characteristic (ROC) curve was applied to evaluate the sensitivity and specificity of the cutoff value.Phase2prospectively observed the hemodynamic effects of anisodemine in STEMI patients undergoing early PCI following thrombolysis. From March2010to December2010, concecutive STEMI patients within12hours after thrombolysis were enrolled. All eligible patients were randomly assigned to anisodamine group (ANI) and control group (CON). Patients in ANI group received intracoronary bolus injection of anisodamine (2000μg,10ml) over2minutes according to the heart rate and blood pressure, and the same vulome of0.9%sodium chloride in the CON group. The other medications and laboratory examinations were the same as phase1. The primary end point was the level of TMPG after PCI, and the second end points were including the hemodymanic parameters, STR, peak level of CK-MB, TIMI flow grade and major adverse cardiac events after PCI. The software of SPSS17.0(SPSS Inc. Chicago, Illinois) was used in the statistic analysis, and P<0.05was consided statistically significant.Result:A total of159patients were enrolled in phase1, with31in poor perfusion group and128in normal perfusion group. Both SBP and DBP before PCI were lower in poor perfusion group than those in normal perfusion group (P<0.001). There was a trend of faster heart rates in the poor perfusion (P=0.098). The LVEF in the normal perfusion group was better than that in the poor group (P=0.005). The other baseline clinical data were similar between the two groups (all.P>0.05). The Killip classification, IRA distribution, baseline TIMI flow grade and thrombosis score were all similar (all P>0.05). There were significant differences in Grade3TIMI flow and CTFC between the two groups. Univariate logistic analysis found that low level of TIMI flow grade, SBP and DBP before PCI were predictors for poor myocardial perfusion, while multivariate logistic regression showed that low level of SBP before PCI and the history of diabetes were predictive factors for poor myocardial perfusion. The predictive model established according to hemodynamic parameters before PCI was as follows:hemodynamic parameter=1+exp (-(-4.091+0.085×DBP+0.016×SBP-0.037×HR)). ROC analyses were performed to determine the best cut-off value of ratio for predicting poor perfusion. The area under the ROC curve for ratio was0.775(95%CI0.683-0.868, P<0.0001). The ratio of0.789was determined to be the best discriminating value for predicting poor perfusion, with a sensitivity of78.1%and a specificity of71.0%.Seventy-six patients were prospectively enrolled in Phase2, with39in ANI group and37in CON group. No significant differences in baseline clinical data and baseline angiography data were found (all P>0.05). Compared to CON group, the rate of TMPG3was higher in ANI group, while the CTFC was lower (both P<0.05). There was a mild increase of heart rate, SBP and DBP after administration of anisodamine (all P<0.05). The hemodynamic parameter decreased according to the predictive model in phase1. There were sinificant differences in the peak level of CK-MB, LVEF, and STR in the ANI group. The incidences of MACE were similar between the two groups.Conclusion:1. Low level of DBP before PCI was one of independent predict facter for imcomplete perfusion.2. Intracoronary administration of anisodamine before PCI could improve the myocardil perfusion which may be result in the hemodynamic effects of anisodamine. Part ⅢAdditive benefit of glycoprotein Ⅲb/Ⅲa inhibition and adjunctive Objectives:The aim of the study was to evaluate the additional benefit of preventive administration of anisodamine to tirofiban during primary PCI on myocardial reperfusion.Methods:This study was a prospective, randomized, single blinded study with2×2factorial design. Consecutive STEMI patients undergoing early PCI within12h of thrombolysis and admitted from December2010to December2011were randomly assigned to1of the4intervention groups: primary PCI (PCI), anisodsamine infusion (ANI), tirofiban infusion (TIR) and PCI with both treatments (ANI+TIR). All patients received aspirin (300mg loading followed by100mg daily) and clopidogrel (600mg loading followed by75mg daily). Heparin boluses were administered to maintain an activated clotting time of250s in patients treated with tirofiban, and>300s in the remaining patients. According to the result of angiography, PCI was performed unless the blood flow of infarct-related artery (IRA) achieved TIMI grade3and the residual stenosis of IRA was less than75%. After coronary angiography, but before the first balloon inflation, patients in the ANI group and TIR+ANI group received intracoronary bolus injection of anisodamine (1000μg,5ml) over3minutes, and the same vulome of0.9%sodium chloride in the other two groups. Tirofiban was administered with a10μg/kg bolus intracoronary injection for over3minutes followed by0.075μg·kg-1·min-1infusion for12hours in TIR group and ANI+TIR group and the same vulome of0.9%sodium chloride in the remaining patients. The blood pressure and electrocardiogram were monitored and recorded during PCI. The other medications were administered to the patients (including aspirin, clopidogrel, diuretics, isotropic agents, intravenous vasodilator, lipid-lowering, beta-blockade, and angiotensin of converting enzyme inhibitors) according to current best practice. Serum creatine kinase (CK), MB fraction (CK-MB), and standard12-lead ECGs were recorded at admission, after the procedure, and then every6h for24h. Echocardiographic examination was performed at discharge by a cardiologist blinded to the randomization results. Left ventricular ejection fraction (LVEF) was determined from apical2and4chambers views by Simpson’s biplane formula. The angiographic results before and after PCI by two independent cardiologists who were blinded to the procedures. Thrombosis score, TIMI flow grade (TFG) of IRA before and after PCI, corrected TIMI frame count (CTFC), TIMI myocardial perfusion grade (TMPG) after PCI were recorded. All ECGs were read at the core laboratory by2cardiologists blinded to the randomization. ST-segment resolution (STR) was determined by comparing the ST scores before and after the procedure,>70%decrease of the initial ST elevation was categorized as complete STR. Analyses were done using SPSS for Windows17.0(SPSS Inc., Chicago, Illinois). A two-sided of P-value <0.05was defined as statistically significant.Results:A total of96patients were enrolled (24cases in each group), and all patients received the assigned treatment. No significant difference in baseline clinical characteristics was found among groups, including mean age, gender distribution, risk factors, and clinical presentations (all P>0.05). No different baseline angiographic characteristics were found among groups (all P>0.05). There was a trend of more patients achieving post-procedural TIMI3flow in the ANI+TIR group, compared to the primary PCI group (95.8%vs.75.0%, P=0.084). The post-procedural CTFC in ANI+TIR group was less than the other three groups (P=0.002), while the post-procedural CTFC in both ANI group and TIR group were improved. There was also a possible interaction regarding CTFC with the P=0.165of anisodamine×tirofiban. There was a trend of more complete STR in both ANI group and TIR group than that in primary PCI group, and a significant difference of more complete STR in ANI+TIR group was found than that in primary PCI group (91.7%vs.58.3%, P=0.039). There was a trend of high level of peak CK-MB in primary PCI group (P=0.245). No significant difference of bleeding complications was found among groups. There was a trend of higher LVEF at discharge in the TIR+ANI group, compared to the primary PCI group (56.19%±4.05%vs.50.70%±7.35%, P=0.005). No palpitation, thirst, blurred vision or retention of urine were found in the patients who were administered anisodamine. No malignant arrhythmia (defined as ventricular fibrillation or ventricular tachycardia with hemodynamic compromise requiring defibrillation) occurred in patients treated with anisodamine. No significant difference of occurrence of MACE was found among groups (P=0.686).Conclusions:1. Both anisodamine and tirofiban addministered before PCI may improve the myocardial reperfusion in STEMI patients undergoing early PCI following thrombolysis.2. There are possible interactions of anisodamine and tirofiban on myocardial reperfusion. Part ⅣProtective Effects of Anisodamine on Renal Function in Patients with ST-Segment Elevation Myocardial Infarction undergoing Primary Percutaneous Coronary InterventionObjective:This single blinded, placebo-controlled and randomized trial was to evaluate the effect of anisodamine on renal function in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI).Methods:From March2010to December2011, all consecutive STEMI patients within12hours from onset of symptoms undergoing primary PCI in the Cardiology Department of the Second Hospital of Hebei Medical University were enrolled. Eligible patients were randomly assigned to receive anisodamine (anisodamine group, ANI) or placebo (control group, CON) by means of random number table. Patients in the ANI group received anisodamine50μg/kg bolus injection after randomization followed by an adjusted-dose (0.1-0.2μg/kg/min) to24h after PCI, while patients in CON received infusion of placebo (0.9%sodium chloride) with the same volume of ANI group. Other medications were administered to all the patients (including aspirin, clopidogrel, diuretics, isotropic agents, intravenous vasodilator, statins, beta-blockade, angiotensin converting enzyme inhibitors, and anticoagulation agents) according to current best practice. Primary PCI was performed with standard technique as soon as possible. PCI success was defined as grade3flow of post procedural thrombolysis in myocardial infarction (TIMI) and a decrease of residual stenosis to<20%by quantitative coronary analysis. The nonionic contrast (Ultravist370, iodine370mg/ml, Schering Pharmaceutical Ltd., China) was used in all patients. Intravenous hydration was given to all patients with intravenous isotonic saline (0.9%) at a rate of1ml/kg/hour or0.5ml/kg/hour in case of overt heart failure before the procedure and for12hours after the procedure. Left ventricular function was evaluated by echocardiography in all patients within24hours after admission. Investigators involved in the procedures and those reading echocardiograms were all blind to the randomized treatment. Serum creatinine (SCr) concentrations were measured at admission,24hours,48hours and72hours after PCI. Estimated glomerular filtration rate (eGFR) was calculated by the simplified modification of diet in renal disease study equation (MDRD):eGFR=186×Serum creatinine-1.154×age-0.203(female×0.742). All calculations were computed with the aid of SPSS17.0statistical software. A P Value of less than0.05(2-tailed) was considered statistically significant.Results:Of the177patients enrolled,88were randomly assigned to anisodamine and89to placebo. There were no significant differences in baseline characteristics, including mean age, gender distribution, risk factors, and clinical presentations between the two groups. The laboratory results and medications used during the procedure were not significantly different. The SCr concentration on admission and eGFR were also similar between the two groups. The preexisting chronic kidney disease (defined as eGFR<60ml/min/1.73m2) was not different between the two groups. The average time of onset to balloon was similar between the two groups. There were no significant differences regarding the distribution of infarction related artery, interventions procedure, stent implantations, use of intravenous GP Ⅱb/Ⅲa receptor antagonist, total contrast volume consumption and the hydration volume. The SCr concentration at admission was not significantly different between the two groups. However, it was lower in ANI group than that in CON group at hour48and72after administration of contrast medium (99.5±26.2μmol/L vs.109.6±37.3μmol/L,82.9±15.6μmol/L vs.94.1±25.8μmol/L, both P<0.01). For both groups, SCr concentrations significantly increased after PCI (P<0.0001), with the peak value occurring at hour48, and then began to decrease. To be specific, in ANI group, SCr concentration decreased significantly at hour72, and returned to baseline level (82.9±15.6μmol/L vs.88.1±22.7μmol/L, P>0.05), while in CON group, SCr concentration also decreased significantly at hour72, but the result was still higher than baseline (94.1±25.8μmol/L vs.85.1±18.6μmol/L, P<0.01). The eGFR at admission was also similar between the two groups. The eGFR at hour24,48and72after primary PCI were higher in ANI group than those in control group (91.5±22.1ml·min-1·1.73m-2vs.83.2±21.3ml·min-11.73m-2,80.2±17.6ml·min-1·1.73m-2vs.73.4±18.5ml·min-1·1.73m-2,93.2±18.4ml·min-1·1.73m-2vs.86.3±21.7ml·min-1·1.73m-2, all P0.05). In ANI group, eGFR increased significantly at hour72compared with that at hour48(93.2±18.4ml·min-1±1.73m-2vs.80.2±17.6ml·min-1·1.73m-2, P<0.01), and the result was similar to the baseline level (93.2±18.4ml·min-1·1.73m-2vs.92.1±21.3ml·min-1·1.73m-2, P>0.05). In CON group, eGFR increased significantly (86.3±21.7ml·min-1·1.73m-2vs.73.4±18.5ml·min-1·1.73m-2, P<0.01) at hour72, but was still lower than baseline level (86.3±21.7ml·min-1·1.73m-2vs.92.5±22.5ml·min-1 1.73m-2, P<0.05). The results of multiple logistic regression showed that the history of diabetes and low LVEF before PCI were independent predictors of CIN, and treatment with anisodamine was an independent preventive factor of CIN (OR,0.369;95%CI,0.171to0.794; P=0.011). The incidences of CIN was20.5%(18/88) and33.7%(30/89) in ANI and CON group respectively, and the incidence of CIN in ANI group was lower than that in CON group within72hours after the procedure (P<0.05). Dialysis was not used in both groups. There was a mild increase of heart rate after administration of anisodamine (73.0±12.3beats/min vs.76.4±9.1beats/min, P<0.05), and the peak value occurred after bolus of anisodamine (73.0±12.3beats/min vs.87.0±16.1beats/min, P<0.05), and recovered6hours later after withdrawal of anisodamine. No malignant arrhythmia occurred in all patients.Conclusion:1. Both diabetes and low LVEF are indipendent predictors for CIN.2. Intravenous infusion of anisodamine before and after primary PCI may reduce the occurrence of CIN in STEMI patients undergoing primary PCI safely.