使用滑稽电流抑制剂伊伐布雷定靶向心率控制以降低非心脏手术患者的发病率：一项2a期、三盲、安慰剂对照随机试验的研究方案

BJA open Pub Date : 2025-02-19 DOI:10.1016/j.bjao.2025.100378

Bernardo Bollen Pinto , Benjamin Shelley , Priyanthi Dias , Salma Begum , Florence Ennahdi-Elidrissi , Tom E.F. Abbott , Russell Hewson , Akshaykumar Patel , Kamran Khan , Rupert M. Pearse , Gareth L. Ackland

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引用次数: 0

摘要

背景：心肌损伤与非心脏手术后的高发病率和死亡率密切相关。高心率可导致围手术期心肌损伤。另外，较高的心率可能反映自主神经功能障碍，促进心肌损伤独立于心率。特异的超极化激活、环核苷酸门控(HCN)-4（有趣）通道抑制剂伊伐布雷定在不改变自主控制、血压或心肌收缩性的情况下减慢心率。我们假设自主神经功能障碍患者可能从伊伐布雷定降低心率控制中获益最多，以最大限度地减少心肌损伤相关的发病率。方法：本研究为三盲、国际、多中心、随机、安慰剂对照、平行组随机试验，招募年龄≥55岁、在择期非心脏手术中存在心血管危险因素的心肌损伤患者350例。为了达到目标心率70次/ min - 1（窦性心律），患者将以1:1的比例随机分配，并将从手术早晨开始接受伊伐布雷定（2.5-7.5 mg）或安慰剂片，每天两次，持续72小时。手术前和术后72小时将测量高灵敏度肌钙蛋白T浓度，对参与者、临床医生和研究人员不透明。主要结局是随机分组后7天内心肌损伤与发病率相关（由术后发病率调查定义）。次要结局包括肌钙蛋白浓度峰值、30天内的并发症和手术后6个月内的死亡率。预先指定的分析将包括静息和直立心率加上手术前脑利钠肽n端原激素浓度。结论：这项2b期研究将探讨在不改变围手术期自主神经控制的情况下，使用伊伐布雷定选择性地减慢心率是否能降低手术后的发病率。临床试验注册号：isrctn12903789。

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Targeted heart rate control using the funny current inhibitor ivabradine to reduce morbidity in patients undergoing noncardiac surgery: study protocol for a phase 2a, triple-blind, placebo-controlled randomised trial

Background

Myocardial injury is strongly associated with excess morbidity and mortality after noncardiac surgery. Higher heart rate may result in perioperative myocardial injury through demand–supply mismatch. Alternatively, higher heart rates may reflect autonomic dysfunction that promotes myocardial injury independently of heart rate. The specific hyperpolarisation-activated, cyclic nucleotide-gated (HCN)-4 (funny) channel inhibitor ivabradine slows the heart rate without altering autonomic control, blood pressure, or myocardial contractility. We hypothesise that individuals with autonomic dysfunction may benefit most from ivabradine reducing heart rate control to minimise myocardial injury-associated morbidity.

Methods

This triple-blind, international, multicentre, randomised, placebo-controlled, parallel group randomised trial will recruit 350 patients, aged ≥55 yr, with cardiovascular risk factors for myocardial injury during elective noncardiac surgery. To achieve the target heart rate <70 beats min⁻¹ (sinus rhythm), patients will be randomly allocated in a 1:1 ratio using minimisation and will receive either ivabradine (2.5–7.5 mg) or placebo tablet twice daily, from the morning of surgery for 72 h. High-sensitivity troponin T concentrations will be measured before and up to 72 h after surgery, blinded to participants, clinicians, and investigators. The primary outcome is myocardial injury associated with morbidity within 7 days of randomisation (defined by Postoperative Morbidity Survey). Secondary outcomes include peak troponin concentrations, complications within 30 days, and mortality within 6 months of surgery. Pre-specified analyses will include resting and orthostatic heart rate plus N-terminal prohormone of brain natriuretic peptide concentrations before surgery.

Conclusions

This phase 2b study will explore whether targeted heart rate control reduces morbidity after surgery, using ivabradine to selectively slow the heart rate without altering perioperative autonomic control.