Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03371784
Recruitment Status : Active, not recruiting
First Posted : December 13, 2017
Last Update Posted : September 28, 2020
Sponsor:
Collaborator:
Romanian Governmental Funding (UEFISCDI)
Information provided by (Responsible Party):
Adrian Corneliu Iancu, Iuliu Hatieganu University of Medicine and Pharmacy

Tracking Information
First Submitted Date  ICMJE December 4, 2017
First Posted Date  ICMJE December 13, 2017
Last Update Posted Date September 28, 2020
Actual Study Start Date  ICMJE March 8, 2018
Actual Primary Completion Date December 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 12, 2017)
The extent of interstitial edema [ Time Frame: 3-5 days ]
Cardiac magnetic resonance (CMR) assessment (% of left ventricular end-diastolic mass)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 12, 2017)
  • The extent of microvascular obstruction [ Time Frame: 3-5 days ]
    Cardiac magnetic resonance (CMR) assessment (% of left ventricular end-diastolic mass)
  • The extent of intramyocardial haemorrhage [ Time Frame: 3-5 days ]
    Cardiac magnetic resonance (CMR) assessment (% of left ventricular end-diastolic mass)
  • Infarct size [ Time Frame: 3-5 days ]
    CMR assessment (% of left ventricular end-diastolic mass)
  • Myocardial salvage [ Time Frame: 3-5 days ]
    CMR assessment (area at risk minus infarct size divided by area at risk multiplied by100)
  • Left ventricular ejection fraction [ Time Frame: 3-5 days and 6 months after the procedure ]
    CMR and echocardiographic assessment (%)
  • Left ventricular end-systolic volume [ Time Frame: 3-5 days and 6 months after the procedure ]
    CMR and echocardiographic assessment (ml)
  • Left ventricular end-diastolic volume [ Time Frame: 3-5 days and 6 months after the procedure ]
    CMR and echocardiographic assessment (ml)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Effect of Glucocorticoid Therapy on Left Ventricular Remodelling in Acute Myocardial Infarction (RECONSIDER)
Official Title  ICMJE The Effect of Glucocorticoid Therapy on Left Ventricular Remodelling in Acute ST-segment Elevation Myocardial Infarction (RECONSIDER)
Brief Summary

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.

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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
1:1 model randomization
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • ST-segment Elevation Myocardial Infarction
  • Left Ventricular Remodeling
Intervention  ICMJE
  • Drug: Hydrocortisone
    I.V. administration
    Other Name: no other name
  • Drug: Placebo
    I.V. administration
    Other Name: sodium chloride 0.9%
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Hydrocortisone
  • 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%).
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 20, 2020)
77
Original Estimated Enrollment  ICMJE
 (submitted: December 12, 2017)
188
Estimated Study Completion Date  ICMJE December 2020
Actual Primary Completion Date December 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Romania
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03371784
Other Study ID Numbers  ICMJE PN-III-P4-ID-PCE-2016-0393
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Adrian Corneliu Iancu, Iuliu Hatieganu University of Medicine and Pharmacy
Study Sponsor  ICMJE Iuliu Hatieganu University of Medicine and Pharmacy
Collaborators  ICMJE Romanian Governmental Funding (UEFISCDI)
Investigators  ICMJE
Principal Investigator: Adrian Corneliu Iancu, M.D, Ph.D "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca
PRS Account Iuliu Hatieganu University of Medicine and Pharmacy
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP