Dabigatran for the Prevention of Myocardial Injury after Orthopedic Surgery (DMINS-PRE). A Study Protocol For A Randomized, Active-Controlled, Phase II Trial

Bayarmagnai Munkhjargal ,Mohamed Aabdien,Daniela Anamaria Hosseyni,Daniela Regina Brandão Tavares,Rui Nakamura,Weitao Chen,John Christopher Polanco Santana,Gabriela Yamaguti Hayakawa ,Augusto César De Andrade Mota ,Craig Devoe ,Cristina Pires Camargo ,Vinícius Andreoli Schoeps ,Sonja Salandy ,Rania Ibrahim ,Maria Regina Alcântara ,Igor D Bandeira

doi:10.21801/ppcrj.2019.52.2

Abstract

Background and Aims: Myocardial Injury after Noncardiac Surgery (MINS) is a broader term that includes not only perioperative myocardial infarction but also other prognostically significant myocardial injuries due to ischemia, within 30 days after noncardiac surgery. Annually, around 1 million patients who undergo noncardiac surgery worldwide die during the first 30 days following surgery. The incidence of MINS is around 5-8%, with the majority occurring in the first two days after surgery. A recent study showed a potential positive effect of Dabigatran to prevent major vascular complications among patients with MINS. However, until now there is no evidence related to whether any effective drug may reduce its incidence. Our study aims to assess the efficacy of dabigatran to prevent MINS in a high cardiovascular risk population. Methods: This study will be a multicenter randomized, two-arms (1:1 ratio), active-controlled and double-dummy, phase II trial. We will study 264 adults (45-75 years) with a high cardiovascular risk, assessed by the Framingham Risk Score, who are undergoing elective orthopedic surgery. Patients which troponin measurement keeps negative after surgery will be randomly assigned (1:1) to receive dabigatran 150mg twice daily or enoxaparin daily, 6 hours after surgery for seven days. The primary outcome will be the incidence of MINS as ascertained by the difference in troponin (troponin delta) greater than 14ng/L in the perioperative period, after randomization. Secondary outcomes will be 30-day mortality, major thromboembolic complications, and severe bleeding complications. The potential impact of the study: This clinical trial will be the first to assess the efficacy and the safety of dabigatran to prevent MINS. Given MINS is estimated to affect every year about 8 million patients worldwide and is associated with cardiovascular complications and death after surgery, we believe this trial will provide relevant data to clinical practice and future research directions.

Highlights

In patients of age ≥ 45 years who undergo noncardiac surgery, there is at least a 5-8% risk of cardiac death, myocardial infarction (MI), heart failure or severe dysrhythmia, such as ventricular tachycardia
There is an additional group of noncardiac surgery patients who have a rise in postoperative high-sensitive cardiac troponin T due to ischemia, but without signs and symptoms of cardiac ischemia
These two groups have been combined into the larger clinical entity of myocardial injury after noncardiac surgery (MINS), which includes both symptomatic and asymptomatic elevations in troponin levels due to ischemia only, within 30-days after surgery, as previously established by the Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) study (Botto et al, 2014)

Summary

Introduction

Background and rationale In patients of age ≥ 45 years who undergo noncardiac surgery, there is at least a 5-8% risk of cardiac death, myocardial infarction (MI), heart failure or severe dysrhythmia, such as ventricular tachycardia. The (Myocardial Injury after Noncardiac Surgery) MANAGE trial had reported that the use of dabigatran (110 mg twice daily) was safe and efficacious compared with placebo in reducing major vascular events among patients that had already developed MINS (Devereaux et al, 2018). We propose a randomized, single-center, two-arm (1:1 ratio), active-controlled, double-dummy, phase II trial of dabigatran for MINS prevention in a high cardiovascular risk population. Our study aims to assess the efficacy of dabigatran to prevent MINS in a high cardiovascular risk population Methods: This study will be a single-center randomized, two-arm (1:1 ratio), active-controlled and double-dummy, phase II trial. Secondary outcomes will be 30-day mortality, major thromboembolic complications, and severe bleeding complications Discussion: This clinical trial will be the first to assess the efficacy and the safety of dabigatran to prevent MINS. Given MINS is estimated to affect every year about 8 million patients worldwide and is associated with cardiovascular complications and death after surgery, we believe this trial will provide relevant data to clinical practice and future research directions

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