Rationale, design, and methods for the early surgery in infective endocarditis study (ENDOVAL 1): A multicenter, prospective, randomized trial comparing the state-of-the-art therapeutic strategy versus early surgery strategy in infective endocarditis

doi:10.1016/j.ahj.2008.04.006

American Heart Journal

Volume 156, Issue 3, September 2008, Pages 431-436

https://doi.org/10.1016/j.ahj.2008.04.006 Get rights and content

Background

The prognosis of infective endocarditis is poor and has remained steady over the last 4 decades. Several nonrandomized studies suggest that early surgery could improve prognosis.

Methods

ENDOVAL 1 is a multicenter, prospective, randomized study designed to compare the state-of-the-art therapeutic strategy (advised by the international societies in their guidelines) with the early-surgery strategy in high-risk patients with infective endocarditis. Patients with infective endocarditis without indication for surgery will be included if they meet at least one of the following: (1) early-onset prosthetic endocarditis; (2) Staphylococcus aureus endocarditis; (3) periannular complications; (4) new-onset conduction abnormalities; (5) new-onset severe valvular dysfunction. A total of 216 patients will be randomized to either of the 2 strategies. Stratification will be done within 3 days of admission. In the early surgery arm, the surgical procedure will be performed within 48 hours of randomization. The only event to be considered will be death within 30 days. The study will be extended to 1 year. In the follow-up substudy, death and a new episode of endocarditis will be regarded as events.

Conclusion

ENDOVAL 1, the first randomized study on endocarditis, will provide crucial information regarding the putative benefit of early surgery over the state-of-the-art therapeutic approach in high-risk patients with infective endocarditis.

Section snippets

Background

Whereas mortality has been dramatically reduced in some areas of cardiac diseases thanks to continuous progress in treatment, endocarditis remains a high-mortality disease with steady percentages of mortality in the last 30 years.1, 2, 3 Several reasons may help to account for this frustrating comparison. The changing pattern of the epidemiology of endocarditis surely has contributed to the still high mortality.4, 5 Patients are older, prosthetic and nosocomial endocarditis are currently more

Study hypothesis

Our hypothesis is that early surgery in high-risk patients with active infective endocarditis decreases mortality and should be considered the treatment of choice in this population.

Study objectives

Our objective was to compare the 30-day mortality rate in high-risk patients with active infective endocarditis between an early surgical approach (surgery performed within the first 48 hours after inclusion or 5 days after the initial diagnosis) and the state-of-the-art treatment in this disease (medical treatment

Determination of sample size

The study will be powered to address the primary hypothesis that a decision to operate on patients with high-risk endocarditis on an urgent basis will decrease inhospital mortality compared to patients managed with the state-of-the-art strategy. Thus, the sample size was calculated based on the assumption of a 30% mortality in the state-of-the-art group¹¹^,17, 18, 19, 20, 21, 22 versus 13% in the early surgery group12, 13 (17% absolute reduction). Table IV shows the mortality rate in high-risk

Study limitations

It has been decided to exclude patients with stroke, either ischemic or hemorrhagic, because it may potentially bias the results. Thus, the results of this study will not be applicable to patients with active endocarditis and stroke, a challenge in the management of this disease.

We would like to test the usefulness of early surgery in the early phase of the disease. Conceptually, therefore, patients whose diagnosis is established after >5 days shall be excluded. Again, our results will not be

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Cited by (38)

Which trial do we need? Elective early surgical treatment of left-sided infective endocarditis
2023, Clinical Microbiology and Infection
Gentamicin may have no effect on mortality of staphylococcal prosthetic valve endocarditis
2018, Journal of Infection and Chemotherapy
Citation Excerpt :
Gentamicin is recommended in SPVE based on synergistic interaction of antibiotic combinations illustrated in in vitro studies, animal models, and observational cohorts [6–19,26–28]. To date, no randomized clinical trials have been conducted into the role of gentamicin in SPVE and it is unlikely that any will be performed due to its low incidence and the high rate of SPVE complications [29]. To address this and other similar issues, the study of large case registries, such as ours, constitutes the basis of the best available evidence [30].
To analyze the influence of adding gentamicin to a regimen consisting of β-lactam or vancomycin plus rifampicin on survival in patients suffering from Staphylococcal prosthetic valve endocarditis (SPVE).
From January 2008 to September 2016, 334 patients with definite SPVE were attended in the participating hospitals. Ninety-four patients (28.1%) received treatment based on β-lactam or vancomycin plus rifampicin and were included in the study. Variables were analyzed which related to patient survival during admission, including having received treatment with gentamicin.
Seventy-seven (81.9%) were treated with cloxacillin (or vancomycin) plus rifampicin plus gentamicin, and 17 patients (18.1%) received the same regimen without gentamicin. The causative microorganism was Staphylococcus aureus in 40 cases (42.6%) and coagulase-negative staphylococci in 54 cases (57.4%). Overall, 40 patients (42.6%) died during hospital admission, 33 patients (42.9%) in the group receiving gentamicin and 7 patients in the group that did not (41.2%, P = 0.899). Worsening renal function was observed in 42 patients (54.5%) who received gentamicin and in 9 patients (52.9%) who did not (p = 0.904). Heart failure as a complication of endocarditis (OR: 4.58; CI 95%: 1.84–11.42) and not performing surgery when indicated (OR: 2.68; CI 95%: 1.03–6.94) increased mortality. Gentamicin administration remained unrelated to mortality (OR: 1.001; CI 95%: 0.29–3.38) in the multivariable analysis.
The addition of gentamicin to a regimen containing vancomycin or cloxacillin plus rifampicin in SPVE was not associated to better outcome.
Current status of infectious endocarditis: New populations at risk, new diagnostic and therapeutic challenges
2018, Enfermedades Infecciosas y Microbiologia Clinica
Infective Endocarditis
2014, Microbiology for Surgical Infections: Diagnosis, Prognosis and Treatment
Infective endocarditis is a medical and surgical condition associated with the inflammation of the endocardium. Typically, the endocardial structures mostly affected are the heart valves. This may lead to various degrees of valvular tissue damage resulting in marked and serious complications, some of which are fatal.
The diagnosis of endocarditis is often challenging due to the frequent lack of classic manifestations on presentation and ongoing evolution of causative organisms, especially with the current wide antibiotic use. Many patients have an underlying congenital or acquired valvular abnormality acting as a predisposition for infection, and those with prosthetic valves, immune-suppression and IV drug use are particularly at risk.
A thorough history and examination combined with investigations, specifically blood cultures and echocardiography, form the basis of the current Duke’s diagnostic criteria. A high level of clinical suspicion is also essential for diagnosis.
Intravenous antibiotics, supportive therapy and occasional surgical intervention form the mainstay of therapy for infective endocarditis and a multi-disciplinary team approach is vital.
The aim of this chapter is to highlight the importance of this illness as one of the leading causes of morbidity and mortality in infectious disease, the urgent need and methods for diagnosis and to review various management options.
Epidemiology of infective endocarditis in Spain in the last 20 years
2013, Revista Espanola de Cardiologia
La endocarditis infecciosa es una enfermedad poco frecuente, con una incidencia estimada de entre 3,1 y 3,7 episodios cada 100.000 habitantes y año, que es máxima en personas de edad avanzada. Los microorganismos que más frecuentemente causan la infección son las diferentes especies de estafilococos y estreptococos. En las últimas décadas ha cambiado el espectro de las cardiopatías que predisponen a padecer una endocarditis, ya que las cardiopatías degenerativas son las valvulopatías más frecuentes y ha aumentado de manera notable el número de pacientes con endocarditis infecciosa sin valvulopatía conocida previamente. Por otro lado, hasta un tercio de los pacientes con endocarditis infecciosa adquieren la infección como consecuencia de un contacto estrecho con el sistema sanitario, y estos pacientes son más frágiles, hecho que condiciona una mayor mortalidad hospitalaria. Como consecuencia de estos importantes cambios epidemiológicos, la profilaxis antibiótica es capaz de prevenir pocos casos de endocarditis infecciosa. Pese a indudables avances en el tratamiento médico y quirúrgico, la mortalidad hospitalaria de los pacientes con endocarditis infecciosa es elevada. Aun así, hay margen de mejora en la prevención de bacteriemias hospitalarias, la detección precoz de la infección en pacientes con riesgo conocido, la identificación rápida de enfermos con mayor riesgo de complicaciones y la formación de equipos multidisciplinarios para el manejo de esta enfermedad.
Full English text available from: www.revespcardiol.org/en
Infective endocarditis is an uncommon disease, with an estimated incidence of 3.1 to 3.7 episodes per 100 000 inhabitants/year. The incidence is highest in elderly people. The microorganisms most frequently isolated in infective endocarditis are staphylococci and streptococci. In the last few decades, the spectrum of heart diseases predisposing to infective endocarditis has changed, since degenerative heart disease is the most common valve disease, and there are an increasing number of infective endocarditis patients without previously known valve disease. In addition, up to one-third of infective endocarditis patients become infected through contact with the health system. These patients are more frail, which leads to higher in-hospital mortality. As a result of substantial epidemiological changes, few cases of infective endocarditis can be prevented by antibiotic prophylaxis. Despite advances in medical and surgical treatment, in-hospital mortality among infective endocarditis patients is high. Nevertheless, there is room for improvement in reducing the rate of nosocomial bacteremia, the prompt diagnosis of infective endocarditis in at-risk patients, and the early identification of patients with a highest risk of complications, as well as in the creation of multidisciplinary teams for the management of this disease.
Mitral valve repair in the course of active infectious endocarditis. Study of four patients
2013, Medicina Clinica
La reparación valvular mitral es el tratamiento de elección de la insuficiencia mitral degenerativa. Sin embargo, no está tan clara su indicación en el caso de insuficiencias mitrales (IM) secundarias a endocarditis infecciosas (EI), particularmente cuando se intervienen durante su fase activa. Si bien varios estudios observacionales han mostrado la superioridad de la reparación con respecto a la sustitución mitral en pacientes sometidos a cirugía de EI, en la mayoría de los centros se sigue optando por la sustitución valvular por su facilidad y reproducibilidad técnica. Exponemos a continuación la experiencia de nuestro centro.
Se trata de 4 pacientes intervenidos recientemente durante la fase activa de una endocarditis infecciosa. Se discuten las características epidemiológicas y clínicas de cada paciente.
Los 4 pacientes fueron sometidos a distintas técnicas de reparación valvular mitral. No se han descrito recaídas ni reinfecciones, y todos los pacientes presentan IM de grado 0 o i/iv en el seguimiento.
La reparación valvular mitral durante la fase activa de la EI es una técnica factible y que permite obtener buenos resultados postoperatorios.
Mitral valve (MV) repair is the preferred surgical treatment for degenerative mitral regurgitation (MR). However, questions remain about the efficacy of MV repair when performed for MR caused by infective endocarditis (IE), particularly during its active phase. Although several observational studies have suggested the superiority of MV repair over replacement in patients undergoing surgery for IE, many centres are still opting for valve replacement because of its technical feasibility and reproducibility. In the following document we expose the experience of our hospital.
We present a series of 4 patients who recently underwent surgery for IE during its active phase. Epidemiological and clinical characteristics are discussed.
All patients underwent different MV repair techniques. No relapse or reinfection has been reported. All patients present MR grades 0 or iI/ivIV at follow up.
Even during the active phase of IE, MV repair is a feasible technique with good postoperatory results.

View all citing articles on Scopus

: This study was financed in part by the Cooperative Network for Cardiovascular Research (Red Cooperativa de Enfermedades Cardiovasculares, RECAVA) of the Spanish National Institute of Health (Instituto de Salud Carlos III). ClinicalTrials.gov identifier: NCT 00624091.

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Trial DesignRationale, design, and methods for the early surgery in infective endocarditis study (ENDOVAL 1): A multicenter, prospective, randomized trial comparing the state-of-the-art therapeutic strategy versus early surgery strategy in infective endocarditis

Background

Methods

Conclusion

Section snippets

Background

Study hypothesis

Study objectives

Determination of sample size

Study limitations

Clin Microbiol Infect

Ann Thorac Surg

Cardiovasc Surg

Ann Thorac Surg

Am J Med

Evaluating and optimizing outcomes of surgery for endocarditis

JAMA

Identification of high-risk subgroups in infective endocarditis and the role of echocardiography

Eur Heart J

Infective endocarditis. A prospective study at the end of the twentieth century

Medicine

Staphylococcus aureus endocarditis: a consequence of medical progress

JAMA

Circulation

Guidelines on prevention, diagnosis and treatment of infective endocarditis executive summary; the task force on infective endocarditis of the European society of cardiology

Eur Heart J

Risk stratification and bedside prognostication in infective endocarditis

JAMA

Trial Design
Rationale, design, and methods for the early surgery in infective endocarditis study (ENDOVAL 1): A multicenter, prospective, randomized trial comparing the state-of-the-art therapeutic strategy versus early surgery strategy in infective endocarditis