Matrix Metalloproteinase Inhibition With Doxycycline to Prevent Adverse Remodeling After Acute Myocardial Infarction: A Pilot Study
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 174
- 试验地点
- 1
- 主要终点
- Left ventricular end-systolic volume index (LVESVi)
研究概览
简要总结
Current medical treatment allows more people to survive heart attacks than in the past. However, some of the survivors suffer heart disease and require hospitalization later on. The causes behind this heart disease (heart failure) after a heart attack are poorly understood.
Matrix metalloproteinase 2 (MMP-2) is a protein that cuts other proteins into pieces, and is activated in heart muscle when there is a heart attack. MMP-2 causes heart injury when the blood flow to the heart is restored after the attack. Blocking MMP-2 activity is a potential therapy to prevent heart injury under these circumstances. The only MMP-2 inhibiting drug currently approved for clinical use is doxycycline, specifically used to treat periodontitis (gum inflammation) and rosacea (a skin condition). At higher doses doxycycline also acts as an antibiotic for which it has been clinically used for decades.
A previous clinical study found that taking doxycycline twice a day, for one week after a heart attack improved the health of the patients' hearts. The investigators have conducted a similar study in patients that had surgery to replace blocked coronary arteries (blood vessels that feed the heart muscle). These patients took a low dose of doxycycline once a day for 2 days before surgery, on the day of the surgery, and three days after surgery. The participants in this study showed no adverse effects of using doxycycline.
The goal of this study is to see if doxycycline protects the hearts of patients that suffered a heart attack. All patients will receive standard clinical care for their condition, but in addition will take a doxycycline capsule twice a day, or a placebo capsule for 7 days, as soon as possible after being diagnosed with a heart attack. Three months later, the investigators will evaluate the patients by looking at their heart structure using magnetic resonance imaging (MRI). MRI is a powerful tool that allows doctors to see inside the body without surgery or X-ray radiation. The hearts of those patients that received doxycycline are expected to be healthier than those who received placebo.
The investigators plan to promote the use of doxycycline to protect the hearts of patients with heart attacks. If successful, doxycycline could help improve the quality of life of heart attack survivors.
详细描述
Background:
Matrix metalloproteinases (MMPs) are activated in myocardial ischemia, digesting key structural components in cardiac muscle in the setting of myocardial infarction and myocardial ischemia-reperfusion injury (Schulz, 2007, Annu. Rev. Pharmacol. Toxicol. 47, 211-42).
The antibiotic doxycycline is the only drug approved as an MMP inhibitor by Health Canada and the U.S. FDA for the treatment of periodontitis and rosacea at sub-antimicrobial doses.
Doxycycline decreases intracellular proteolysis, improves cardiac function, and reduces infarct size in animal models of ischemia-reperfusion injury (Cheung et al, 2002, Circulation 101:1833-39; Villarreal et al, 2003, Circulation 208:1487-92).
TIPTOP (Cerisano et al, 2014, Eur Heart J 35: 184-91) was a randomized open-label trial (110 patients) that studied the effect of 1-week doxycycline given post-percutaneous coronary intervention (PCI) in patients with anterior STEMI. Patients who received doxycycline showed improved echocardiographic indices at 6 months relative to untreated controls: left ventricular end diastolic volume index (LVEDVi) -8 mL ± 14 mL (P=0.004), left ventricular end systolic volume index (LVESVi) -6 mL ± 12 mL (P=0.02), and left ventricular ejection fraction (LVEF) +5% ± 12% (P=0.04). They also showed decreased infarct sizes (-6%, P=0.05) by single photon emission computed tomography (SPECT).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double-blinding. Randomization will be done prior to the study and with binary encoding, for further blinding. Drug randomization (placebo or doxycycline) will be done by the Drug Development and Innovation Centre in the Faculty of Pharmacy and Pharmaceutical Sciences at the University of Alberta, with 50% allocated in the Placebo Control Group and 50% in the Doxycycline Group. The coding list will be generated and kept sealed by the PI. Patients will be randomized during recruitment, following a previously generated list with 50% of patients allocated to each group.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •18+ year old
- •Diagnosis of acute ST-elevation myocardial infarction (STEMI)
- •Primary STEMI
- •Symptom onset of less than 12 hours
- •Admitted to the Royal Alexandra Hospital in Edmonton, Alberta
排除标准
- •Low risk inferior STEMI (total ST elevation plus depression <4mm)
- •Cardiogenic shock
- •Use of thrombolytics
- •Prior history of myocardial infarction or heart failure
- •Known hypersensitivity to tetracyclines
- •Any concurrent medical condition expected to reduce life expectancy to <1 year
- •Symptom onset to treatment (loading dose) time longer than 24 hours
- •Poor renal function (eGFR<30 mL/min/1.73m2) or other contraindications to MRI (claustrophobia, pregnancy, PPM/ICD, sub-arachnoid clips, retained ocular foreign body)
研究组 & 干预措施
Doxycycline hyclate
Two 100mg doxycycline capsules (200 mg) p.o. upon enrollment, followed by one 100 mg capsule p.o. every 12 hours for 7 days
干预措施: Placebo (Drug)
Placebo control
Two placebo capsules upon enrollment, followed by one placebo capsule p.o. every 12 hours for 7 days
干预措施: Doxycycline Hyclate (Drug)
结局指标
主要结局
Left ventricular end-systolic volume index (LVESVi)
时间窗: 3 months post intervention
Left ventricular end-systolic volume index (LVESVi) measured by magnetic resonance imaging (MRI) at 3 months post intervention
次要结局
- Left ventricular ejection fraction (LVEF)(3 months post intervention)
- Left ventricular end-diastolic volume index (LVEDVi)(3 months post intervention)
- Infarct size(3 months post intervention)
- Composite endpoint of mortality and hospital admission due to re-infarction, heart failure, or stroke(3 months and one year post intervention)