Clinical trial NCT03411499: Stroke-free Survival Comparison Between Early Surgery and Conventional Therapy in Left Infective Endocarditis
Official title: Stroke-free Survival Comparison Between Early Surgery and Conventional Therapy in Left Infective Endocarditis - A Multicenter Partially Randomized Preference Trial (EARLY Study)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Endocarditis
Keywords: Adult
Endocarditis/surgery
Embolism/prevention & control
Cardiovascular Diseases
Costs and Cost Analysis
Quality of life
Lead sponsor: Maria Vittoria Hospital
Sponsor class: OTHER
Collaborators: name: Ministry of Health, Italy
First posted: 2018-01-26
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Partially Randomized Preference Trial
Primary purpose: TREATMENT

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

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.

Eligibility criteria: 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

Primary outcomes:
measure: Stroke-free survival
timeFrame: 12 months
Secondary outcomes:
measure: Overall survival
timeFrame: 12 months
measure: In-hospital mortality
timeFrame: During follow-up, until discharge from hospital, up to 1 year from randomization date
measure: Embolic event during the hospitalization of IE diagnosis
timeFrame: During follow-up, until discharge from hospital, up to 1 year from randomization date
measure: Stroke during the hospitalization of IE diagnosis
timeFrame: During follow-up, until discharge from hospital, up to 1 year from randomization date
measure: Heart failure during the hospitalization of IE diagnosis
timeFrame: During follow-up, until discharge from hospital, up to 1 year from randomization date
measure: Cumulative incidence of stroke
timeFrame: 12 months
measure: Cumulative incidence of embolic events
timeFrame: 12 months
measure: Cumulative incidence of heart failure
timeFrame: 12 months
measure: Cumulative incidence of IE relapse
timeFrame: 12 months
measure: Quality of Life using 36-Item Short Form Survey (SF-36)
timeFrame: 0, 4, 12 months
measure: Quality of Life using EuroQol five dimension (EQ-5D).
timeFrame: 0, 4, 12 months
measure: 1-year event-free survival
timeFrame: 12 months
measure: Cost-effectiveness
timeFrame: 12 months
measure: Length of hospitalization
timeFrame: During follow-up, until discharge from hospital, up to 1 year from randomization date
measure: Number of hospital readmission for length .of stay within 1 year for any cause
timeFrame: 12 months
measure: Feasibility of early surgery
timeFrame: During follow-up, until discharge from hospital, up to 1 year from randomization date
Other outcomes:
Locations:
city: Torino
country: Italy
facility: SC Cardiochirurgia U - AOU Città della Salute e della Scienza di Torino - PO Molinette
Study officials:
affiliation: Maria Vittoria Hospital
name: Enrico Cecchi, MD
role: PRINCIPAL_INVESTIGATOR
References: