key: cord-1020240-m8rb5zop authors: Xu, Yi; Li, Xiangdong; Zhang, Haitao; Wu, Yuan; Zhang, Jun; Li, Jia; Dou, Kefei; Yan, Hongbing; You, Shijie; Yang, Yanmin; Liang, Yan; Xu, Lianjun; Gao, Xiaojin; Liu, Chen; Dong, Qiuting; Zhang, Wenjia; Song, Guangyuan; Zhang, Tao; Jiang, Lin; Chen, Guihao; Tang, Ruijie; Jin, Chen; Yang, Jingang; Yao, Chen; Xian, Ying; Peterson, Eric D.; Gao, Runlin; Yang, Yuejin title: China Tongxinluo study for myocardial protection in patients with acute myocardial infarction (CTS-AMI): Rationale and Design of a Randomized, double-blind, placebo-controlled, multi-center clinical trial date: 2020-06-20 journal: Am Heart J DOI: 10.1016/j.ahj.2020.06.011 sha: 0b4b883e04ff89a351b807f610757b993889dd01 doc_id: 1020240 cord_uid: m8rb5zop Abstract Background Acute ST-segment elevation myocardial infarction (STEMI) remains a serious life-threatening event. Despite coronary revascularization, patients might still suffer from poor outcomes caused by myocardial no-reflow and ischemic/reperfusion injury. Tongxinluo (TXL), a traditional Chinese medicine, has been preliminarily demonstrated to reduce myocardial no-reflow and ischemic/reperfusion injury. We further hypothesize that TXL treatment is also effective in reducing clinical endpoints for the patients with STEMI. Methods and Results. The CTS-AMI trial is a prospective, randomized, double-blind, placebo-controlled, multi-center clinical study in China. An estimated 3796 eligible patients with STEMI from about 120 centers are randomized 1:1 ratio to TXL or placebo groups. All enrolled patients are orally administrated a loading dose of 8 capsules of TXL or placebo together with dual anti-platelet agents on admission, followed by 4 capsules three times a day until 12months. The primary endpoint is 30-day major adverse cardiovascular and cerebrovascular events (MACCE), a composite of cardiac death, myocardial re-infarction, emergency coronary revascularization, and stroke. Secondary endpoints include each component of the primary endpoint, 1-year MACCE and other efficacy and safety parameters. Conclusion Results of CTS-AMI trial will determine the clinical efficacy and safety of traditional Chinese medicine TXL capsule in the treatment of STEMI patients in the reperfusion era. Acute ST-segment elevation myocardial infarction (STEMI) is a major life threatening disease. Timely revascularization of the infarct related artery (IRA) with reperfusion therapy, such as percutaneous coronary intervention (PCI) or thrombolysis, has been demonstrated to improve outcomes for STEMI patients 1, 2 . However, restoration of blood flow in the occluded IRA does not always equal to the recovery of myocardial reperfusion. Paradoxically, it can cause myocardial no-reflow and ischemic/reperfusion (I/R) injury 3 . Myocardial no-reflow phenomenon is mainly due to the damage of microvascular endothelial cells and the injury of the integrity of microvascular structure, function, and barrier, which will then result in the obstruction of microvasculature and the extravasation of both white and red blood cells into myocardium 4 . Besides, it is also clinically acknowledged to be associated with the embolisms of microthrombi and plaque debris, micro-thrombogenesis, compression of myocardial edema, and spasm of microvessels [5] [6] [7] [8] . Although several medications and devices have been studied in preventing myocardial no-reflow [9] [10] [11] [12] [13] [14] [15] [16] [17] , their effects are still controversial. Myocardial I/R injury is traditionally considered to be associated with myocardial inflammation, oxidative stress, calcium overload, and mitochondrial dysfunction [18] [19] [20] [21] [22] . Decades of studies have pinpointed several pathways 23 that can be targeted to blunt myocardial I/R injury by inhibiting the opening of mitochondrial permeability transition pore (MPTP), namely the common reperfusion injury salvage J o u r n a l P r e -p r o o f 3 that TXL could facilitate myocardial reperfusion with the incidence of myocardial no-reflow significantly reduced by 36.6% (34.3% vs. 54.1%) and the infarct size minimized 40, 41 . We further hypothesize that TXL treatment is also effective in reducing the clinical endpoints for patients with STEMI. Therefore, we designed this randomized multi-center clinical trial to evaluate the clinical efficacy and safety of TXL in STEMI patients in China. The CTS-AMI trial is a prospective, randomized, double-blind, placebo-controlled, multi-center clinical study. Its objective is to evaluate the efficacy and safety of TXL capsules in Chinese patients with STEMI. A total of 120 centers (including the principal site) are expected to participate in the present study. The inclusion and exclusion criteria are listed in Table 1 . Patients with STEMI are enrolled after preliminary screening to meet all the inclusion criteria and none of the exclusion criteria. A package of 3-month amount of TXL or placebo is distributed to each enrolled patient. At every scheduled 3-month follow-up, the residual drugs will be brought back by the patient and another package of 3-month of the research drugs will then be given by investigators. All residual drugs will be retrieved and destroyed at the end of the study by the sponsor. Distribution and retrieval of research drugs will be recorded timely and accurately in the case report form (CRF). All patients are receiving standard treatment for STEMI based on guideline recommendations, including coronary reperfusion (primary PCI or thrombolysis except for the contraindications and other exceptions from patients and physicians) and medical therapies 1, 29 . Usage of thrombus aspiration catheter, distal protective devices, platelet GP Ⅱ b/ Ⅲ a receptor antagonist, and stent implantation during primary PCI is at the interventionalist's discretion. Administration of other TCM or Chinese patent medicine similar in function and indications with the research drug is prohibited during the entire study period. Each patient's medical history and baseline results of physical examination, ECG, and laboratory tests are collected on admission according to Table 2 . ECG will also be taken 2, 12, 24, and 72 hours after admission. Laboratory tests, echocardiogram, and 24-hour dynamic ECG (Holter monitor) are scheduled to be performed on the 7th day of hospitalization or before discharge ( Table 2 ). All surviving patients are followed-up until 1 year regardless of reaching endpoint or not. Outpatient follow-up visits are Journal Pre-proof J o u r n a l P r e -p r o o f 5 scheduled at 1 month (30 ± 3 days), 3 months (± 7 days), 6 months (± 7 days), and 12 months (1 year ± 7 days) after randomization (Figure 1 ). ECG and laboratory tests will be performed at 1, 6, and 12 months. Echocardiogram and Holter will be conducted at the last follow-up visit ( Table 2 ). The primary endpoint of the present study is 30-day major adverse cardiovascular and cerebrovascular events (MACCE), a composite of cardiac death, myocardial re-infarction, emergency coronary revascularization, and stroke. re-hospitalization due to heart failure, all-cause death, and in-stent thrombosis. Besides, myocardial reperfusion and no-reflow rate (ST-segment resolution and occurrence of no-reflow) in electrocardiogram (ECG) will be evaluated at 2, 24 hours, and 7 days after revascularization therapy (Table 3) . Adverse events (AE) refer to any adverse medical event that occurs during the study period, regardless of its relation with the research drug. AE that meets any of the following criteria is defined as a severe adverse event (SAE): 1) Death; 2) Life-threatening situation; 3) Temporary or permanent disabilities; 4) Re-hospitalization or prolonged hospital stay. All AEs will be assessed about their relation with the research drug, recorded in CRF, and be followed-up until recovery or stabilized. Any SAEs that occur during the study period will be reported to the Sample size of the present study was calculated using PASS13 software (NCSS, Kaysville, UT, USA) based on previous reports 43, 44 . The assumptions included a 30-day MACCE rate of 9% in placebo group and 6.3% in TXL group. Based on these, an estimated sample size of 1,518 patients in each group would give 80% (two-sided α=0.05 and β=0.20) statistical power to detect a significant difference. Accounting for a 20% drop-out rate, increased the sample size to 1898 for each arm, leading to a total target enrollment of 3,796. Continuous variables are described as mean and standard deviation and compared using paired t test or Wilcoxon rank test, as appropriate. Categorical variables are described using frequencies and percentages and compared using chi-square test or Fisher's exact test, as appropriate. Statistical analyses will be carried out using SAS 9.4 (or higher version, SAS Institute, Cary, NC, USA) and a 2-tailed P<0.05 is considered statistically significant. Efficacy analysis in two groups will be statistically described respectively and the inter-group comparison will be performed with the statistical method mentioned above. In accordance with the requirements of adverse drug reaction (ADR) relation, the AEs and ADRs (including the number of cases with various AEs, the number of cases with "normal results to abnormal results" or "aggravation of abnormal results" of laboratory test indicators before and after testing and the abnormal conversion rate) in two groups will be tabulated, and the relevant causes and explanations will be listed. The incidence of AEs will be comparatively analyzed between two groups. Despite the rapid progresses in cardiology and pharmacology, acute STEMI remains a dangerous life-threatening disease. Reperfusion therapy including primary PCI or thrombolysis has been considered the international standard treatment for STEMI patients 2 , though myocardial no-reflow and reperfusion injury may occur following reperfusion therapy. Although rapid progress in experimental studies for myocardial protection has been made lately 19, 20 , there's still no breakthrough in clinical use in this field so far 45 . Moreover, a large number of "reperfusion therapy missing" patients exist in China, particularly at primary hospitals in rural areas. As a traditional Chinese medicine (TCM) compound, TXL was developed according to its theory of "main and collateral channels" and approved for clinical use in China in 1996. It has been proposed to treat coronary artery diseases across China for more than 20 years 46-48 . In accordance with the TCM theory, myocardial no-reflow phenomenon and I/R injury after reperfusion therapy of STEMI patients are considered a kind of "main and collateral channels" disease which is equivalent to microvascular dysfunction and obstruction occurred in the infarcted region. Then we hypothesized that TXL was able to protect and even "dredge these channels", promote myocardial reperfusion, and to be expected for the prevention and treatment of myocardial no-reflow and I/R injury in STEMI patients. The main expected obstacle during the 12-month study period is the drug Journal Pre-proof J o u r n a l P r e -p r o o f 10 compliance of patients, which might lead to inaccurate and misguiding results. In order to avoid this, patient compliance will be assessed during the whole study period. The residual amount of research drugs from each patient will be retrieved and accounted for before drug distribution at each follow-up visit. Drug compliance will then be quantitatively assessed and recorded in the CRF (compliance = actual/estimated amount of research drug taken during the follow-up period ×100%). A compliance >80% is considered consistent with study requirements. Moreover, investigators should thoroughly inform participating patients about the study and drug dosage to ensure satisfying compliance. In conclusion, the CTS-AMI trial is a prospective, randomized, double-blind, placebo controlled, multi-center clinical study to evaluate the clinical efficacy of oral TXL capsule and its safety with clinical hard endpoint in the treatment of STEMI patients with reperfusion therapy or for the reperfusion-missing patients. The results will be expected to verify and provide novel evidence-based treatment options for myocardial no-reflow and reperfusion injury and probably further improve the outcomes of STEMI patients in the reperfusion era. The present study is financially supported by the National Key Research and Development Program of China (No. 2017YFC1700503). The authors have declared no conflicts of interest. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC) ESC/EACTS Guidelines on myocardial revascularization The coronary circulation as a target of cardioprotection The "no-reflow" phenomenon after temporary coronary occlusion in the dog Microvascular obstruction and the no-reflow phenomenon after percutaneous coronary intervention Plaque gruel of atheromatous coronary lesion may contribute to the no-reflow phenomenon in patients with acute coronary syndrome No-reflow phenomenon and lesion morphology in patients with acute myocardial infarction Relation of atherothrombosis burden and volume detected by intravascular ultrasound to angiographic no-reflow phenomenon during stent implantation in patients with acute myocardial infarction Angiographic outcomes with early eptifibatide therapy in non-ST-segment elevation acute coronary syndrome (from the EARLY ACS Trial) Randomized trial of primary PCI with or without routine manual thrombectomy Turco reperfusion in patients undergoing percutaneous coronary intervention in ST-segment elevation acute myocardial infarction with versus without diabetes mellitus (from the EMERALD Trial) Is Aspiration Thrombectomy Beneficial in Patients Undergoing Primary Percutaneous Coronary Intervention? Meta-Analysis of Randomized Trials Thrombus Aspiration for ST-Segment-Elevation Myocardial Infarction in Modern Era: Still an Issue of Debate? Adenosine as an Adjunct Therapy in ST Elevation Myocardial Infarction Patients: Myth or Truth? Cardiovasc Drugs Ther The effect on myocardial perfusion and clinical outcome of intracoronary nicorandil injection prior to percutaneous coronary intervention in ST-segment elevation myocardial infarction Effect of intracoronary nitroprusside in preventing no reflow phenomenon during primary percutaneous coronary intervention: a meta-analysis Cyclosporine before PCI in Patients with Acute Myocardial Infarction Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines Tongxinluo attenuates reperfusion injury in diabetic hearts by angiopoietin-like 4-mediated protection of endothelial barrier integrity via PPAR-alpha pathway Beneficial effects of Tong-xin-luo (herb) on myocardial no-reflow after acute myocardial infarction and reperfusion: experiment of mini-swine model Effect of tongxinluo on endothelin-1 in the mini-swine model of acute myocardial infarction and reperfusion Effect of tongxinluo ultramicro-pulverization on myocardial post-reperfusion no-reflow in mini-swine model of acute myocardial infarction Effects of tongxinluo on mini-swine vascular endothelial integrity and myocardial no-reflow in early reperfusion of acute myocardial infarction Effect of tongxinluo on mini-swine cytokines and myocardial no-reflow in early reperfusion of acute myocardial infarction The protective effects of Tong-xin-luo on myocardium and microvasculature after reperfusion in acute myocardial infarction Effect of Tongxinluo combined with Trimetazidine on cardiac function after percutaneous coronary intervention in acute ST-elevation myocardial infarction Application effect of tongxinluo capsule combines with trimetazidine in postoperative ASETMI patients treated by PCI. Prac J Cardiac Cereb Pneumal Vasc Dis Effects of Tongxinluo capsule combined with tirofiban on thrombus formation and inflammatory factors in patients with acute myocardial infarction after PCI Clinical effects of metoprolol sustained release tablets combined with Tongxinluo on patients of acute myocardial infarction Protective effect of Tongxinluo on myocardium in patients with acute myocardial infarction undergoing thrombolytic therapy Effects of Tongxinluo Capsule on CRP and ventricular remodeling in patients with acute myocardial infarction The effect of Tongxinluo capsules on coronary restenosis of patients with acute myocardial infarction after percutaneoas coronary intervention Clinical effects of Tongxinluo capsule on patients of acute myocardial infarction Age>18 years 2. Within 24 hours of infarctional chest pain onset 3. ECG shows ST-segment elevation ≥0.2mV in more than 2 adjacent leads, or new left bundle branch block 4. Voluntary participation in the study with consent forms signed Exclusion criteria 1. Critically ill and dying 2. CPR >20 min 3. Suspected aortic dissection or acute pulmonary embolism 4. Explicit mechanical complications, including intervenricular septum perforation, rupture of papillary muscles and chordae tendineae, or on-going or ruptured left ventricular free walls 5. Serious cardiogenic shock and do not responsing to hypertensive agents 6. Uncontrolled acute left heart failure or pulmonary edema 7. Malignant arrhythmias uncontrolled by anti-arrhythmia agents 8. Bleeding history of cerebral vessels, gastrointestinal tract, respiratory tract, urinary tract or other organs within 1 month 9. Presence of active hemorrhage at any part of the body (including menstruation) 10. Known hemorrhagic constitution or serious hemostasis and blood coagulation disorders 11 Other pathophysiological conditions with expected survival time <1 year 23. Unsuitability to participate in this study due to other diseases Abbreviations: ECG, electrocardiogram; CPR, cardio-pulmonary resuscitation ULN, upper limit of normal COPD, chronic obstructive pulmonary disease