EASE

Published

Kang DH, et al. "Early surgery versus conventional treatment for infective endocarditis". The New England Journal of Medicine. 2012. 366(26):2466-73.
PubMed • Full text • PDF

Clinical Question

Among patients with left-sided native-valve endocarditis at high risk of embolic events, does early surgery reduce mortality and embolic events as compared to conventional treatment?

Bottom Line

Among patients with left-sided native-valve endocarditis at high risk of embolic events, early surgery reduces mortality and embolic events as compared to conventional treatment.

Major Points

Antibiotics are the mainstay of therapy in infective endocarditis (IE), with surgery historically reserved for those with valvular regurgitation and heart failure or refractory embolic events. To better understand the optimal timing of surgical intervention in this patient population, these investigators sought to study the role of early surgery as a means of preventing mortality and embolic events in patients with native-valve left-sided endocarditis (NVE).

Published in 2012, the Early Surgery versus Conventional Treatment in Infective Endocarditis (EASE) study randomized patients with newly diagnosed left-sided NVE to either early surgery within 48 hours of randomization or conventional therapy alone, consisting of antibiotics and supportive care with surgery only performed for urgent indications or persistent symptoms despite completion of antibiotics. The primary composite endpoint was in-hospital death or occurrence of an embolic event within 6 weeks of randomization. A total of 76 patients were enrolled, 67% were men, 59% had mitral valve-only disease and 29% had aortic valve-only disease, most had severe valvular regurgitation, and median vegetation size was 12 mm. All patients in the early-surgery group underwent surgery within the designated interval, and in the conventional care group, 77% of patients underwent surgery (21% needed urgent surgery, 56% received elective surgery ≥2 weeks after randomization). The primary endpoint occurred less frequently in the early-surgery group compared to the conventional-care group (3% vs. 23%; HR 0.10; P=0.03). At 6 months, there was no difference in survival between groups (3% vs. 5%).

Long-term follow-up indicated an improvement in event-free survival at 7 years and in all-cause mortality, embolic events, or recurrence of IE at 4 years. However, there was no significant difference in all-cause mortality at 4 years. Due to the small sample size and selected patient population of the trial, it is difficult to confirm the effect of early surgery on mortality. A meta-analysis which included the EASE trial reported that early surgery was associated with significant all-cause mortality benefits as compared to conservative therapy. However, most studies on this topic have been observational studies. The authors suggested that more randomized studies are required to validate the findings.

Guidelines

AHA Infective Endocarditis in Adults (2015, adapted)

Regarding early valve surgery in left-sided NVE:

• indicated in valve dysfunction causing heart failure; heart block, annular or aortic abscess, or destructive penetrating lesions; persistent infection despite appropriate antimicrobial therapy (Class I; Level of Evidence B)
• should be considered with fungi or highly resistant organisms (eg, VRE, multidrug-resistant Gram-negative bacilli) (Class I; Level of Evidence B)
• reasonable with recurrent emboli, persistent or enlarging vegetations despite appropriate antibiotics; severe valve regurgitation and mobile vegetations >10 mm (Class IIa, Level of Evidence B)
• may be considered with mobile vegetations >10 mm, particularly when involving the mitral valve anterior leaflet and associated with other relative indications for surgery (Class IIb; Level of Evidence C)

Design

• Prospective, randomized trial
• N=76 patients with left-sided NVE at high risk of complications
  • Early surgery (n=37)
  • Conventional treatment (n=39)
• Setting: 2 centers in Korea
• Enrollment: 2006-2011
• Median follow-up: 749 (425-1242) days
• Analysis: Intention-to-treat
• Primary outcome: In-hospital mortality or embolic events at 6 weeks

Population

Inclusion Criteria

• Age ≥18 years
• Left-sided NVE diagnosed according to the modified Duke criteria
• High risk of embolism with both of the following:
  1. Severe mitral valve or aortic valve disease
  2. Vegetation diameter >10 mm

Exclusion Criteria

Details are presented elsewhere.

• Age >80 years
• Moderate-to-severe heart failure
• Infective endocarditis complicated by heart block, annular or aortic abscess, penetrating lesions requiring urgent surgery
• Fungal endocarditis
• Coexisting major embolic stroke with a risk of hemorrhagic transformation
• Prosthetic valve endocarditis
• Right-sided vegetations
• Vegetations ≤10 mm in diameter
• Referred from another hospital >7 days after the diagnosis of infective endocarditis
• Serious comorbidities (eg, cancer)

Baseline Characteristics

From the early surgery group

• Demographics: Mean age 46 years; women 35%
• Endocarditis-related:
  • Valve involved: mitral 59%, aortic 30%, aortic and mitral 11%; vegetation diameter >10-15 mm in 70%, >15 mm in 30%
  • Valvular stenosis 3%, regurgitation 97%; LVEF 61.7%
  • Embolism: cerebral 30%, renal 16%, splenic 38%; EuroSCORE 6.4±1.6
  • Microorganisms: viridans streptococci 27%, other streptococci 30%, Staphylococcus aureus 8%, enterococcus 5%, Haemophilus parainfluenzae 3%, culture-negative 27%
• Laboratory parameters: serum creatinine 1.28 mg/dL
• Medical history: DM 22%, CAD 8%, HTN 30%, underlying valve disease 95%, immunocompromised 5%

Interventions

• Patients were randomized to:
  • Early-surgery - therapy within 48 hours
  • Conventional treatment - therapy according to the 2005 AHA guidelines; surgery performed only if symptoms persisted despite antibiotic therapy or complications requiring urgent surgery developed
• All patients in the early-surgery group had valve surgery within 48 hours post-randomization; 77% of patients in the conventional treatment group required surgery during initial hospitalization or follow-up.

Outcomes

Comparisons are early surgery vs. conventional treatment

Primary Outcomes

In-hospital mortality or embolic events

3% vs. 23% (HR 0.10; 95% CI 0.01-0.82; P=0.03)

(Manuscript table gives conflicting P value of 0.01.)

Secondary Outcomes

In-hospital mortality

3% vs. 3% (P=1.00)

All-cause mortality at 6 months

3% vs. 5% (HR 0.51; 95% CI 0.05-5.66; P=0.59)

Embolic events at 6 months

All: 0% vs. 21% (P=0.005)

Cerebral: 0% vs. 13%

Coronary: 0% vs. 3%

Popliteal 0% vs. 3%

Splenic 0% vs. 3%

Recurrence of IE at 6 months

0% vs. 3% (P=1.00)

Mortality, embolic event, recurrence of IE at 6 months

3% vs. 28% (HR 0.08; 95% CI 0.01-0.65; P=0.02)

Criticisms

• Generalizability: Eligibility criteria were limited; patients with high operative risk, major stroke, prosthetic valve disease, or aortic abscess were excluded.
• Generalizability: Organisms isolated in this study may not be representative of other locations. For example, viridans streptococci were the predominant microorganisms and the incidence of S. aureus was lower than that reported in other studies.
• Many patients had signs of embolization prior to randomization.
• Only a small number of centers and patients were involved.
• There was no data on the pathological confirmation of valve infection.

Funding

No funding source was specified in the manuscript or supplemental data.