研究将指导心血管疾病全面防治的新策略

Professor Rury Holman University of Oxford, UK Professor Chang Yu Pan Professor Da Yi Hu Chinese PLA General Hospital University of Peking China China Rationale for ACE Trial Accumulating evidence suggests there is a close association between “prediabetes” and cardiovascular disease (CVD) Treating conventional risk factors in type 2 diabetes does not reduce CVD risk to the same level as in a non-diabetic population Post prandial hyperglycaemia may explain the excess risk seen in diabetes and “prediabetes” Acarbose has been reported* to reduce CVD risk in individuals with “prediabetes”, but its impact on new CVD events in individuals with “prediabetes” and existing CVD and is unknown * Chiasson JL et al. JAMA 2003; 290(4): 486-94 ACE Trial Management Coordinating Centre Diabetes Trials Unit, University of Oxford ACE Chinese Project Office Oxford University (Beijing) Science & Technology Limited Funding & Study Medication Bayer HealthCare China & Bayer Schering Pharma Study Design Double-blind, multi-centre, randomised, controlled, clinical outcome trial comparing acarbose versus placebo Investigator designed and led academic trial Independent data collection, analysis and reporting Conducted in Mainland China and Hong Kong 7,500 patients in 150 cardiovascular centres Minimum patient follow up four years Event driven (904 adjudicated primary events) Rury Holman UK Diabetologist (Chair) DaYi Hu China Cardiologist (Co-Chair) ChangYu Pan China Diabetologist (Co-Chair) JiaLun Chen China Diabetologist (Honoured adviser) Juliana Chan Hong Kong Diabetologist Jean-Louis Chiasson Canada Diabetologist JunBo Ge China Cardiologist Hertzel Gerstein Canada Diabetologist John McMurray UK Cardiologist Lars Rydn Sweden Cardiologist Michal Tendera Poland Cardiologist Jaakko Tuomilehto Finland Epidemiologist WenYing Yang China Diabetologist Joanne Keenan UK DTU Project Manager Dieter Neuser Germany Bayer Project Manager Thorsten Petruschke Germany Bayer Project Manager ACE Steering Committee Major Inclusion Criteria Confirmed cardiovascular disease (CVD) - History of myocardial infarction - Previous unstable angina - Current stable angina Impaired glucose tolerance (IGT) on an oral glucose tolerance test with: - Fasting plasma glucose 3x ULN) Severe renal impairment (eGFR 30 ml/min/1.73m2) Gastrointestinal problems or alpha glucosidase inhibitor intolerance Pregnancy or possibility of pregnancy Thought by the investigator to be unsuitable ACE Primary Endpoint Composite “hard” CVD endpoint Defined as the time to the first occurrence after randomisation of any of: Cardiovascular death Resuscitated cardiac arrest Non-fatal myocardial infarction Non-fatal stroke An Endpoint Adjudication Committee, masked to therapy allocation, will review all potential CVD endpoints independently. New-onset type 2 diabetes, confirmed by two successive diagnostic plasma glucose values - FPG 7.0 mmol/l and/or - 2HPG 11.1 mmol/l ACE Secondary Endpoint All cause mortality Extended CVD endpoint of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, fatal or non-fatal stroke and hospitalisation for heart failure or for unstable angina. - Each component will also be analysed individually Evidence of non-alcoholic fatty liver disease (NAFLD) as judged by ALT changes Development of impaired renal function (eGFR 60 ml/minute/1.73 m2) or doubling of baseline creatinine Health Economic evaluation Other Secondary Outcomes Sample Size Estimation Assumes A primary event rate of 3.5% per year A 20% relative reduction compared with placebo An 18 month accrual period Alpha of 5% For 90% Power The study requires 7,268 patients with a minimum of 904 adjudicated primary events A total of 7,500 patients will be recruited to allow for an overall 3% loss-to-follow up Double Blind Intervention In addition to optimised CVD therapy: Randomised to: - Acarbose, 50 mg three times a day or - Matching placebo, three times a day Tablets to be taken with meals Use Start low, go slow dose titration ACE Study Flow Chart Minimum of 904 adjudicated primary events required 7,500 CVD or ACS Optimisation of Cardiovascular Therapy CVD therapy will be optimised during the four-week, single-blind, placebo run-in period to ensure it conforms with international guidelines for treating patients with established CVD That is: Antiplatelet therapy, unless contraindicated or not tolerated A statin, unless contraindicated or not tolerated ACE inhibitor, beta-blocker, and/or antihypertensive therapy if considered indicated by the investigator Safety The ACE trial will be conducted to ICH-GCP standards Liver function will be monitored annually Serious Unexpected Suspected Adverse Reactions (SUSARs) will undergo expedited reporting An Independent Data Safety Monitoring Board (DSMB) will review unblinded safety data at least six-monthly The ACE trial is enrolling 150 cardiovascular centres in Mainland China and Hong King Each centre is expected to recruit approximately 50 patients (minimum of 35 patients) Recruitment is competitive and will close when 7,500 patients have been randomised The ACE trial results are expected in 2014 Schedule Clinical Centre Requirements Qualified research staff and appropriate facilities to safely and properly conduct the trial in accordance with ICH GCP guidelines Proven clinical trial experience or willingness to acquire the necessary skills Access to a sufficient eligible patients to ensure around 50 can be enrolled and kept in the trial for a minimum followed up period of