The Effect of Glucocorticoid Therapy on Left Ventricular Remodelling in Acute Myocardial Infarction (RECONSIDER) (RECONSIDER)

September 25, 2020 updated by: Adrian Corneliu Iancu, Iuliu Hatieganu University of Medicine and Pharmacy

The Effect of Glucocorticoid Therapy on Left Ventricular Remodelling in Acute ST-segment Elevation Myocardial Infarction (RECONSIDER)

Introduction: In the setting of acute ST-segment elevation myocardial infarction (STEMI) coronary wedge pressure (CWP) emerges as a new marker for the advanced form of pre-procedural microvascular obstruction (MVO), which is associated with inflammatory interstitial edema. Through its anti-inflammatory effects, glucocorticoid therapy may prove beneficial in patients with high CWP.

Aim: To identify the presence of the advanced form of MVO before primary percutaneous coronary intervention (PPCI) by CWP measurement and to test the benefit of cortisol therapy, in terms of infarct size and left ventricular remodeling, in patients with raised CWP.

Methods: 50 patients with a first STEMI, candidates for PPCI, with proximal coronary occlusion, will undergo CWP measurement followed by percutaneous revascularization. Cardiac MRI will be performed 3-5 days after the procedure. A cutoff for CWP in predicting MVO, interstitial oedema and intramyocardial haemorrhage will be derived.Based on the above mentioned cutoff, 180 patients with continuous elevation of the pressure line will be randomized, by a 1:1 model, either to cortisol therapy or to placebo. Inflammatory parameters will be determined from peripheral blood samples. Patients will undergo cardiac magnetic resonance (CMR) imaging 3 to 5 days after revascularization.

Study endpoints: The primary endpoint will be the extent of MVO, interstitial edema and hemorrhage. Secondary endpoints will include infarct size, myocardial salvage, left ventricular volumes and ejection fraction. The clinical endpoints of all-cause and cardiovascular death, myocardial re-infarction, target vessel revascularization, stent thrombosis and stroke will be recorded at 6 months.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

PATIENT POPULATION Consecutive patients with first STEMI, candidates for PPCI (typical cardiac chest pain, within 12h of symptom onset, with ST segment elevation of more than 1 mm in at least two contiguous leads) and proximal coronary artery culprit lesion will be considered for randomization.

Exclusion criteria are cardiogenic shock. previous myocardial infraction, previous PCI and coronary artery bypass surgery (CABG), left bundle branch block, active bleeding, administration of thrombolytic agents for the current episode, recent stroke (during last month), indication for oral anticoagulant therapy, severe or untreated infections and the impossibility of CWP measurement.

Verbal assent will be obtained, with the agreement of two qualified cardiologists. Full consent will be obtained after the procedure, in accord with the protocols followed by several recent studies.

This is a triple-blind clinical study. The physicians performing the procedure, the subjects and the biostatistician will be blinded to the treatment administered.

The study will take place in a high-volume university hospital center that provides 24-hours emergency cardiac care in a region with 1.3M inhabitants: "Niculae Stãncioiu" Heart Institute - Cardiology Department. The hospital is affiliated to "Iuliu Haţieganu" University of Medicine and Pharmacy, Cluj-Napoca.

STUDY PROTOCOL Patients will receive a standard dual antiplatelet therapy regimen protocol with ticagrelor (180mg) and aspirin (300 mg) loading before PPCI and will be treated with intravenous heparin 100UI/kg during the procedure. Coronary catheterization and intervention will be performed using a 6-F guiding catheter via radial or femoral access.

According to the type of the culprit lesion, three different techniques will be used:

  1. Coronary occlusion: the lesion is crossed with a pressure guidewire (Verrata Pressure Guide Wire, Volcano Corporation) - CWP is recorded if TIMI flow remains 0.
  2. Coronary occlusion: the lesion can not be crossed with the pressure guidewire - the lesion is crossed with a standard coronary guidewire, a dual-lumen microcatheter (NHancer Rx Dual Lumen Micro Catheter, Interventional Medical Device Solutions) is positioned distal to the occlusion, backflow is obtained and CWP measurement is performed, through the micro-catheter only if the occlusion persists. A pressure guidewire is introduced through the over-the-wire lumen of the micro-catheter and CWP is again recorded.
  3. Coronary stenosis (circulated vessel): the lesion is crossed with a pressure guidewire and CWP is measured during the inflation of the predilatation balloon or during stent balloon inflation in case of a direct stenting procedure.

Following CWP measurement, blood samples are collected from a peripheral vein for hsCRP, IL-6, IL-18 and IL-1Ra determination.

The first 50 patients will not receive study treatment. They will undergo CWP measurement followed by percutaneous revascularization. Cardiac MRI will be performed 3-5 days after the procedure. A cutoff for CWP in predicting MVO, interstitial oedema and intramyocardial haemorrhage will be derived.

Based on the above mentioned cutoff, 188 patients with continuous elevation of the pressure line will be randomized, by a 1:1 model, either to cortisol therapy or to placebo.

Group A (GA) will be randomized to hydrocortisone during the first 5 days, and Group B (GB) will be randomized to placebo. Following CWP determination, patients in GA will have an intravenous injection of 500 mg of hydrocortisone followed by an intravenous infusion of 500 mg of hydrocortisone in 250 ml of 5% sugar solution over eight to ten hours. This treatment will be repeated daily for the next five days. This protocol was used by Barzilai et al. which reported a significant mortality reduction with therapy.

PCI will be performed according to standard practice, at the discretion of the operator, following CWP measurement. Heparin will be given as an initial bolus of 100 U/kg during the procedure and if necessary, additional boluses will be administered to achieve an activated clotting time of 300sec.

Appropriate secondary prevention will be performed with statins, angiotensin-converting enzyme inhibitors, beta-blockers and dual anti platelet therapy for 1 year.

CARDIAC MAGNETIC RESONANCE (CMR) IMAGE AQUISITION AND ANALYSIS Patients will undergo CMR three to five days after randomization for the evaluation of the primary endpoint (MVO, interstitial edema and hemorrhage) and selected secondary endpoints (infarct size, left ventricular ejection fraction and volumes). A standard protocol will be used on a 1.5T scanner.

In brief, infarct size and MVO will be assessed by late enhancement in short-axis images covering the left ventricle approximately 15 min after injection of gadolinium chelate. An inversion-recovery turbo gradient-echo sequence will be used for image acquisition. A hypo-intense core within the hyper-enhanced infarcted area will be defined as MVO. For determination of infarct-related myocardial edema/area at risk, short-axis slices covering the LV using a T2-weighted triple- inversion recovery turbo spin-echo sequence before contrast administration will be obtained. Assessment of LV function and volumes will be performed in short-axis slices from base to apex acquired by a standard steady-state free precession technique.

MVO and infarct size will be expressed as percentage of LV mass, given by the sum of the mass of MVO and late gadolinium enhancement regions for all slices divided by the overall mass of the LV myocardial cross-section slices. If present, myocardial salvage index will be calculated as area at risk minus infarct size divided by area at risk multiplied by100.

STUDY ENDPOINTS The primary endpoint will be the extent of MVO, interstitial edema and hemorrhage assessed by CMR in the modified intention-to-treat population. The correlation between CWP, interstitial edema and surrogate parameters of inflammation from peripheral blood samples will be analyzed. Secondary CMR endpoints will include infarct size, myocardial salvage, LV volumes and ejection fraction. LV ejection fraction and volumes will be determined both at discharge and 6 months after the procedure. For enzymatic infarct size determination, high-sensitivity troponin T after 24 and 48 h will be measured. Clinical endpoints of all-cause and cardiovascular death, myocardial re-infarction, target vessel revascularization, stent thrombosis and stroke will be recorded at 6 months.

STATISTICAL ANALYSIS The number of patients that would be needed to detect a difference of 21% between GA and GB for the clinical end-point, with a α of 0.05, a β of 0.20 and a 1:1 ratio was calculated using the formula provided by Whitley and Ball. The necessary number of patients, under the risk of dropout of 10%, led to a number of 94 patients per arm.

Intention-to-treat analysis will be applied in the analysis of both primary and secondary end-points. Statistical analyses will be performed using "Statistical" software (StatSoft v.8, OK, USA). Quantitative variables will be summarized as mean and standard deviation for normally distributed data and median and interquartile range for abnormally distributed data. Groups will be compared with the Student-t test for independent samples in case of normally distributed quantitative variables. Otherwise, the comparison will be performed with the Mann-Whitney test. Categorical variables will be summarized as frequencies and percentage with 95% associated confidence intervals. Groups will be compared with the Chi-square or Fischer exact test, as appropriate. Statistical analysis will be conducted at a significance level of 5%.

Study Type

Interventional

Enrollment (Actual)

77

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Romania
    • Cluj
      • Cluj-Napoca, Cluj, Romania, 400001
        • "Niculae Stancioiu" Heart Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 85 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • age: 18-85 years
  • first episode of ST-segment elevation myocardial infarction
  • candidates for primary PCI (typical cardiac chest pain, within 12h of symptom onset, with ST-segment elevation of more than 1 mm in at least two contiguous leads)
  • left anterior descending artery culprit lesion

Exclusion Criteria:

  • cardiogenic shock
  • previous PCI and coronary artery bypass surgery (CABG)
  • left bundle branch block
  • active bleeding
  • administration of thrombolytic agents for the current episode
  • recent stroke (during last month)
  • indication for oral anticoagulant therapy
  • severe or untreated infection
  • the impossibility of CWP measurement.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: TRIPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
ACTIVE_COMPARATOR: Hydrocortisone
Patients who meet the inclusion criteria, with a CWP above the derived cutoff, with continuous elevation of the pressure line, who are randomized to i.v hydrocortisone administration.
Drug: Hydrocortisone
I.V. administration
Other Names:
  • no other name
PLACEBO_COMPARATOR: Placebo
Patients who meet the inclusion criteria, with a CWP above the derived cutoff, with continuous elevation of the pressure line, who are randomized to placebo (sodium chloride 0.9%).
Drug: Placebo
I.V. administration
Other Names:
  • sodium chloride 0.9%

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The extent of interstitial edema
Time Frame: 3-5 days
Cardiac magnetic resonance (CMR) assessment (% of left ventricular end-diastolic mass)
3-5 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The extent of microvascular obstruction
Time Frame: 3-5 days
Cardiac magnetic resonance (CMR) assessment (% of left ventricular end-diastolic mass)
3-5 days
The extent of intramyocardial haemorrhage
Time Frame: 3-5 days
Cardiac magnetic resonance (CMR) assessment (% of left ventricular end-diastolic mass)
3-5 days
Infarct size
Time Frame: 3-5 days
CMR assessment (% of left ventricular end-diastolic mass)
3-5 days
Myocardial salvage
Time Frame: 3-5 days
CMR assessment (area at risk minus infarct size divided by area at risk multiplied by100)
3-5 days
Left ventricular ejection fraction
Time Frame: 3-5 days and 6 months after the procedure
CMR and echocardiographic assessment (%)
3-5 days and 6 months after the procedure
Left ventricular end-systolic volume
Time Frame: 3-5 days and 6 months after the procedure
CMR and echocardiographic assessment (ml)
3-5 days and 6 months after the procedure
Left ventricular end-diastolic volume
Time Frame: 3-5 days and 6 months after the procedure
CMR and echocardiographic assessment (ml)
3-5 days and 6 months after the procedure

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Iuliu Hatieganu University of Medicine and Pharmacy

Collaborators

Romanian Governmental Funding (UEFISCDI)

Investigators

  • Principal Investigator: Adrian Corneliu Iancu, M.D, Ph.D, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

March 8, 2018

Primary Completion (ACTUAL)

December 31, 2019

Study Completion (ANTICIPATED)

December 1, 2020

Study Registration Dates

First Submitted

December 4, 2017

First Submitted That Met QC Criteria

December 12, 2017

First Posted (ACTUAL)

December 13, 2017

Study Record Updates

Last Update Posted (ACTUAL)

September 28, 2020

Last Update Submitted That Met QC Criteria

September 25, 2020

Last Verified

September 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PN-III-P4-ID-PCE-2016-0393

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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