Effect of Heart Rate Control With Ivabradine on Myocardial Injury After Non-cardiac Surgery: a Single Center, Randomized Controlled, Double-blind Feasibility Pilot Trial
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 78
- 试验地点
- 1
- 主要终点
- Appropriate dosage rate
研究概览
简要总结
Perioperative myocardial injury (PMI) after non-cardiac surgery (NCS), i.e. the elevation of postoperative troponin, occurs in nearly 20% of patients older than 45 years undergoing NCS and is independently and strongly associated with post-operative mortality (30-day mortality up to 10%). With over 300 million surgical interventions every year worldwide, PMI has a high clinical relevance on the health of the population.
Heart rate (HR) is an independent and modifiable risk factor for PMI and death after non-cardiac surgery. Numerous studies showed that beta-blockers decrease myocardial ischemia after surgery in a heart-rate dependent manner, but this beneficial effect is surpassed by an increased incidence of perioperative hypotension and death. Currently, no single intervention is available to decrease the risk of perioperative cardiac complications. Ivabradine (IVA) is a negative chronotropic agent without significant effects on contractility or vascular tone and has been shown to improve outcomes in the setting of chronic and acute heart diseases.
Rationale for pilot feasibility trial: the planned definitive large trial is a multicenter trial to investigate the efficacy of ivabradine to decrease perioperative myocardial injury. The intervention planned is complex and demands important resources. The investigators designed this pilot study to inform on the feasibility of the definitive large trial. This pilot study will also provide additional information that could help investigators improve the definitive large trial regarding recruitment, refinements to the study protocol and improving the participant's experience.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 45 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Informed Consent as documented by signature of patient; AND
- •Undergoing intermediate or high-risk non-cardiac surgery (as defined in European Society of Anaesthesiology guidelines) AND;
- •One of the following:
- •o≥ 75 years old OR; o≥ 45 years old AND at least 1 risk factors independently associated with perioperative myocardial injury (history of coronary artery disease, chronic heart failure, peripheral artery disease, ischemic stroke, hypertension, diabetes mellitus, chronic kidney disease).
排除标准
- •Inability to provide informed consent;
- •History of hypersensitivity or allergy to ivabradine;
- •Emergency surgery (to be done within 24h of diagnosis);
- •Shock or acute decompensated heart failure at trial inclusion;
- •Low cardiac output syndrome;
- •Arrhythmia:
- •Atrial fibrillation or flutter;
- •AV-block of 3rd degree;
- •Sick sinus syndrome;
- •Sino-atrial block;
- •Pacemaker dependency;
- •Unstable angina;
- •Acute myocardial infarction in the 3 months preceding the trial;
- •Stroke in the 3 months preceding the trial;
- •Cirrhosis Child B and C;
- •Renal failure with a Estimated Glomerular filtration rate ≤ 15 ml/min/1.73m2;
- •Treatment with a strong cytochrome P450 3A4 inhibitors such as azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin; josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone;
- •Treatment with verapamil or diltiazem which are moderate CYP3A4 inhibitors and PGP inducers with heart rate reducing properties;
- •Women who are pregnant or breast feeding;
- •Childbearing potential (Of note, woman with history of hysterectomy, surgical sterilization or menopause for longer than 2 years are not considered with childbearing potential, independent of their age);
- •Participation in another study with investigational drug within the 30 days preceding and during the present study;
- •Previous enrolment into the current study.
研究组 & 干预措施
Ivabradine
Ivabradine will be administered in an individualized regimen adapted to the subject's heart rate at each visit in a dosage ranging from 0-7.5mg twice daily (morning and evening) from the morning of surgery until post-operative day 2, as follows:
- If heart rate is ≥101 bpm: capsule D (Ivabradine 7.5 mg);
- If heart rate is 86-100 bpm: capsule C (Ivabradine 5 mg);
- If HR is 71-85 bpm: capsule B (Ivabradine 2.5 mg);
- If HR ≤ 70 bpm or the patient received rescue treatment for bradycardia (eg.atropine) after the previous dose: capsule A (placebo).
干预措施: Ivabradine (Drug)
Ivabradine
Ivabradine will be administered in an individualized regimen adapted to the subject's heart rate at each visit in a dosage ranging from 0-7.5mg twice daily (morning and evening) from the morning of surgery until post-operative day 2, as follows:
- If heart rate is ≥101 bpm: capsule D (Ivabradine 7.5 mg);
- If heart rate is 86-100 bpm: capsule C (Ivabradine 5 mg);
- If HR is 71-85 bpm: capsule B (Ivabradine 2.5 mg);
- If HR ≤ 70 bpm or the patient received rescue treatment for bradycardia (eg.atropine) after the previous dose: capsule A (placebo).
干预措施: Placebo (Drug)
Placebo
Placebo will be administered twice daily (morning and evening) from the morning of surgery until post-operative day 2, as follows:
- If heart rate is ≥101 bpm: capsule D (Placebo)
- If heart rate is 86-100 bpm: capsule C (Placebo)
- If HR is 71-85 bpm: capsule B (Placebo)
- If HR ≤ 70 bpm or the patient received rescue treatment for bradycardia (eg.atropine) after the previous dose: capsule A (Placebo).
干预措施: Placebo (Drug)
结局指标
主要结局
Appropriate dosage rate
时间窗: From the morning (6-9 am) of the day of surgery of the first study participant to the evening of the second post-operative day of the last study participant (up to 1 year from first randomization).
Number of correct dosages administered according to the patient's heart rate at each study visit divided by the total dosages administrated
Blinding success rate
时间窗: From the morning (6-9 am) of the day of surgery of the first study participant to the evening of the second post-operative day of the last study participant (up to 1 year from first randomization).
Number of times blinding code was broken divided by the total dosages administrated
次要结局
- Recruitment rate(Up to one year from the date participant screening begins.)
- Participant satisfaction regarding information about the study, informed consent, recruitment procedures and study participation(Screening, morning of the day surgery pre-operatively and post-operative days 1, 2 and 3.)
- Perioperative myocardial injury(Day of surgery pre-operatively (between 6-9 am) and post-operatively (between 6-9 pm or within 1h after surgery if surgery ends after 9pm) and morning (between 6-9 am) of post-operative days 1, 2, 3 and day of hospital discharge.)
- Heart rate(Day of surgery pre-operatively (between 6-9 am) and post-operatively (between 6-9 pm or within 1h after surgery if surgery ends after 9pm) and morning (between 6-9 am) of post-operative days 1, 2, 3 and day of hospital discharge.)
- Quality of Recovery(Morning (between 6-9 am) of post-operative days 1, 3 and at day of hospital discharge.)
- Ivabradine dosage(Day of surgery pre-operatively (between 6-9 am) and morning (between 6-9 am) of post-operative days 1 and 2.)
- Difficulty in following study protocol and administrating study drug(Morning (between 6 and 9 am) and evening (between 6 and 9 pm) of day of sugery and post-operative days 1 and 2.)
研究者
Bernardo Bollen Pinto, MD PhD
Senior Registrar and Research Fellow
University Hospital, Geneva