Stroke-free Survival Comparison Between Early Surgery and Conventional Therapy in Left Infective Endocarditis

Stroke-free Survival Comparison Between Early Surgery and Conventional Therapy in Left Infective Endocarditis - A Multicenter Partially Randomized Preference Trial (EARLY Study)

The purpose of the EARLY study is to evaluate the efficacy and effectiveness of early surgery in patients with Infective Endocarditis (IE).

Study Overview

• Status: Terminated
• Conditions: Endocarditis
• Intervention / Treatment: Procedure: Early surgery; Procedure: Conventional therapy

Detailed Description

Infective endocarditis (IE) is a relatively rare disease and has a high in-hospital mortality (15-30%) and morbidity due to complications like embolic events, especially in the central nervous system, and heart failure. International guidelines give indications on the optimal timing for surgery, and they strongly recommend early surgery for patients in the active phase of IE with acute cardiac complications (e.g., acute heart failure, uncontrolled infection, and persistent large vegetations after an embolic event). However, at present there is no clear evidence supporting the effectiveness of early surgery or indicating the best time to perform surgery, especially in patients without such conditions. Primary objective of the study is to evaluate whether, in patients with IE and no emergency surgery indication, an early surgical strategy (performed within 72 hours from IE diagnosis) is more effective than conventional therapy in terms of 1-year stroke-free survival. Secondary objectives are: overall survival, risk of embolic, risk of strokes, event-free survival, IE relapse, heart failure, length of hospital stay, hospital re-admission and hospitalization days, strategy compliance, quality of life and health care costs.

This study design consist of a two-arm, open-label, multicenter randomized controlled trial, but patients who decline to be randomized and prefer a certain therapy strategy will be treated according to best practice and included into a prospective observational study after given informed consent. This parallel constructed observational study will be performed with a maximum of consistency to treatment and observation compared to the Randomized clinical trial (RCT). Patients who agree to the randomized trial will be stratified according to centre and clinical features (prosthetic valve,vegetations, valve regurgitation) and randomized with a 1: 1 ratio to 2 different strategies.

According to O'Brien and Fleming group sequential design with a maximum of two stages and a drop-out rate of 10%, a total of 400 randomized patients (200 per group) are required to detect an increase in the stroke-free survival from 82% to 89.5% (corresponding to an Hazard Ratio=0.56) considering a significance level of 5% and a power of 80% and expecting a risk for mortality or stroke at one year with standard treatment equal to 0.18.

EARLY study may help to demonstrate early surgery impact on the contemporary management of the disease.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Enrico Cecchi, MD; Phone Number: +39 0114393315; Email: cecchi.enrico@tin.it
• Study Contact Backup: Name: Davide Forno, MD; Phone Number: +39 0114393315; Email: fornodavide@yahoo.com

Study Locations

• Italy
  • Torino, Italy, 10126
    • SC Cardiochirurgia U - AOU Città della Salute e della Scienza di Torino - PO Molinette

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Left-sided Infective Endocarditis (IE) according to modified Duke criteria, fulfilling at least one of the following features:

   • IE on native or prosthetic valve with severe mitral or aortic valve regurgitation, without heart failure;
   • IE on native or prosthetic valve, during the first week of antibiotic therapy, have very large (15-30 mm) or large (>10mm), mobile isolated vegetations due to Staphylococcus aureus, Streptococcus bovis, HACEK or Abiotrophia, without any other indication for surgery;
   • IE on native or prosthetic valve with severe valve regurgitation without heart failure and with large vegetations (> 10 mm) and Euroscore I 5-19;
   • IE on native or prosthetic valve with moderate o moderate-severe valve regurgitation with large vegetations (> 10 mm)
   • IE on prosthetic valve due to Staphylococcus aureus or gram negative non HACEK microorganisms.
2. Compliance to study treatments
3. Euroscore I <20
4. Informed consent signature

Exclusion Criteria:

1. Patients with right-side IE and IE on a cardiac device

2. Patients with IE and:

   • heart failure , refractory pulmonary oedema, cardiogenic shock or untreatable heart failure
   • fistula involving cardiac chambers or pericardium
   • persistent heart failure or unstable echocardiographic signs or poor haemodynamic tolerance
   • uncontrolled local infection (abscess, pseudoaneurism, fistula, increase in size vegetations)
   • fever and positive blood cultures lasting >7 days
   • fungal IE or other multi-resistant microorganisms
   • large vegetations (> 10 mm) after embolic event
   • large vegetations (> 10 mm) and other predictors of complicated course (heart failure, abscess)
   • vegetations >30 mm

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Early surgery; Surgery within 72 hours from endocarditis diagnosis	Procedure: Early surgery; Surgery within 72 hours from endocarditis diagnosis
Active Comparator: Conventional therapy; Medical treatment and a possible delayed surgical intervention according to the current guidelines	Procedure: Conventional therapy; Delayed surgical intervention or medical treatment according to the current guidelines

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stroke-free survival	Time from randomization until the first occurrence of stroke or death. Stroke is defined as a focal neurologic deficit, lasting at least 24 hours and is categorized as ischemic, hemorrhagic or of uncertain type.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Time from randomization until death from any cause	12 months
In-hospital mortality	Proportion of death during the hospitalization of IE diagnosis	During follow-up, until discharge from hospital, up to 1 year from randomization date
Embolic event during the hospitalization of IE diagnosis	Proportion of patients with clinical and instrumental diagnosis of embolic events after IE diagnosis during the same hospitalization	During follow-up, until discharge from hospital, up to 1 year from randomization date
Stroke during the hospitalization of IE diagnosis	Proportion of patients with clinical and instrumental diagnosis of stroke during the hospitalization of IE diagnosis. Stroke is defined as a focal neurologic deficit, lasting at least 24 hours and is categorized as ischemic, hemorrhagic or of uncertain type.	During follow-up, until discharge from hospital, up to 1 year from randomization date
Heart failure during the hospitalization of IE diagnosis	Proportion of patients with diagnosis of Heart failure during the hospitalization of IE diagnosis.	During follow-up, until discharge from hospital, up to 1 year from randomization date
Cumulative incidence of stroke	Probability that a patient will have a stroke at 12 months from randomization assuming they do not die from some other cause.	12 months
Cumulative incidence of embolic events	Probability that a patient will have an embolic events at 12 months from randomization assuming they do not die from some other cause.	12 months
Cumulative incidence of heart failure	Probability that a patients will have a heart failure at 12 months from randomization assuming they do not die from some other cause.	12 months
Cumulative incidence of IE relapse	Probability that a patient will have an IE relapse at 12 months from randomization assuming they do not die from some other cause.	12 months
Quality of Life using 36-Item Short Form Survey (SF-36)	SF-36 is a generic 36-item questionnaire measuring health-related quality of life (HRQL) composed by 8 subscales. Participants self-report on items that have between 2-6 choices per item using Likert-type responses. Summations of item scores of the same subscale give the subscale scores. Two composite scores, physical component summary (PCS) and mental component summary (MCS), can be derived by a linear combination of the 8 subscales. The PCS is represented by 4 subscales: physical function, role limitations due to physical problems, pain, and general health perception. The MCS is represented by 4 subscales: vitality, social function, role limitations due to emotional problems, and mental health. Both subscales and composite scores are transformed into a range from 0 to 100; zero= worst HRQL, 100=best HRQL.	0, 4, 12 months
Quality of Life using EuroQol five dimension (EQ-5D).	Quality of life will be evaluated using EuroQol five dimension (EQ-5D), a patient-completed, multidimensional measure of health related quality of life. The instrument is applicable to a wide range of health conditions and treatments and results in a single index score. The EQ-5D descriptive health profile comprises five dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension comprises three levels (no problems, some/moderate problems, extreme problems). A unique EQ-5D health state is defined by combining one level from each of the five dimensions. EQ-5D index values range from -0.38 to 1.00 (Italian utility weights). Higher EQ-5D Index scores represent better health status.	0, 4, 12 months
1-year event-free survival	Time from randomization until the first occurrence of one of the following event: , embolic event, IE relapse and heart failure or death.	12 months
Cost-effectiveness	Incremental cost-effectiveness ratio calculated as the ratio between difference in costs and difference in Quality Adjusted Life Years, from EQ-5D (QALYs) among the treatment groups, during the first year after randomization	12 months
Length of hospitalization	Number of days from the date of the randomization and the discharge date	During follow-up, until discharge from hospital, up to 1 year from randomization date
Number of hospital readmission for length .of stay within 1 year for any cause	Number of days of hospitalization for any cause from the the date of discharge	12 months
Feasibility of early surgery	Ratio between the number of patients randomized to early surgery arm and operated within 72 hours and the number of patients randomized to early surgery arm	During follow-up, until discharge from hospital, up to 1 year from randomization date

Collaborators and Investigators

• Sponsor: Maria Vittoria Hospital
• Collaborators: Ministry of Health, Italy
• Investigators: Principal Investigator: Enrico Cecchi, MD, Maria Vittoria Hospital

Publications and helpful links

Helpful Links

• A web application to collect data for experimental studies

Study record dates

Study Major Dates

• Study Start (Actual): December 22, 2017
• Primary Completion (Actual): December 14, 2020
• Study Completion (Actual): December 14, 2020

Study Registration Dates

• First Submitted: December 22, 2017
• First Submitted That Met QC Criteria: January 25, 2018
• First Posted (Actual): January 26, 2018

Study Record Updates

• Last Update Posted (Actual): November 18, 2023
• Last Update Submitted That Met QC Criteria: November 16, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Cardiovascular Diseases; Quality of life; Adult; Costs and Cost Analysis; Endocarditis/surgery; Embolism/prevention & control
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Infections; Bacterial Infections; Bacterial Infections and Mycoses; Cardiovascular Infections; Endocarditis, Bacterial; Endocarditis
• Other Study ID Numbers: Protocol RF-2013-020358691

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No