EASE

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

Infective endocarditis (IE) is a serious disease associated with significant morbidity and mortality. At the time of the study, surgery was indicated in patients with IE complicated by valvular regurgitation causing heart failure. However, the role of surgery for the prevention of systemic embolism has been debatable. The authors were interested in comparing early surgery and conventional treatment in patients with left-sided native-valve endocarditis (NVE).

Published in 2012, the early surgery versus conventional treatment in infective endocarditis (EASE) trial randomized patients to receive early surgery (n=37) or conventional treatment (n=39). The primary outcome was in-hospital mortality or embolic events at 6 weeks. Early surgery reduced the primary outcome significantly as compared to conventional treatment (3% vs. 23%; HR 0.10; 95% CI 0.01-0.82; P=0.03).

Recently, the investigators reported significant benefits of early surgery as compared to conventional treatment on event-free survival at 7 years and all-cause mortality, embolic events or recurrence of IE at 4 years. However, there was no significant difference in all-cause mortality rates at 4 years between the 2 groups.[1] 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.[2] 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.[3]


Guidelines

AHA Infective Endocarditis in Adults (2015, adapted)

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
    • 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
    • Severe mitral valve or aortic valve disease
    • Vegetation with a diameter >10 mm


Exclusion Criteria

Details are presented elsewhere.[4]

  • 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: Age 45.5±14.9 years; males 65%
  • Endocarditis-related:
    • Valve involved: mitral 59%, aortic 30%, aortic and mitral 11%; vegetation diameter >10-15 mm 70%, >15 mm 30%
    • Valvular stenosis 3%, regurgitation 97%; LVEF 61.7±5.1%
    • 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±1.85 mg/dl
  • PMH: DM 22%, CAD 8%, underlying valve disease 95%, hypertension 30%, immunocompromised state 5%


Interventions

  • Patients were randomized to:
    • Early-surgery - therapy within 48 hours
    • Conventional treatment - therapy according to the 2005 AHA guidelines;[5] 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
In-hospital mortality
3% vs. 3%; P=1
Embolic events:
All: 0% vs. 21%; P=0.005
Cerebral: 0% vs. 13%
Coronary: 0% vs. 3%
Popliteal 0% vs. 3%
Splenic 0% vs. 3%

Secondary Outcomes

Mortality, embolic event, recurrence of IE at 6 months
3% vs. 28%; HR 0.08; 95% CI 0.01-0.65; P=0.02
All-cause mortality at 6 months
3% vs. 5%; HR 0.51; 95% CI 0.05-5.66; P=0.59
Embolic event at 6 months
0% vs. 21%; P=0.005
Recurrence of IE at 6 months
0% vs. 3%; P=1

Criticisms

  • The patient population was limited- patients with high operative risk, major stroke, prosthetic valve disease, or aortic abscess were excluded.[6]
  • The relative frequencies of causative microorganisms were affected. Viridans streptococci were the predominant microorganism and the incidence of S. aureus was lower than that reported in other studies.[6][7]
  • The difference in the primary outcome between the 2 groups was significantly driven by a decrease in embolic events with early surgery.[2]
  • Many patients had signs of embolization prior to randomization.[2]
  • Only a small number of centers and patients were involved.[7]
  • There was no data on the pathological confirmation of valve infection.[7]

Funding

Further Reading

  1. Kang DH et al. Long-Term Results of Early Surgery versus Conventional Treatment for Infective Endocarditis Trial. Korean Circ J 2016. 46:846-850.
  2. 2.0 2.1 2.2 Baddour LM et al. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association. Circulation 2015. 132:1435-86.
  3. Anantha Narayanan M et al. Early versus late surgical intervention or medical management for infective endocarditis: a systematic review and meta-analysis. Heart 2016. 102:950-7.
  4. Supplementary Appendix
  5. Baddour LM et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 2005. 111:e394-434.
  6. 6.0 6.1 Kang DH et al. Early surgery versus conventional treatment for infective endocarditis. N. Engl. J. Med. 2012. 366:2466-73.
  7. 7.0 7.1 7.2 Gordon SM & Pettersson GB Native-valve infective endocarditis--when does it require surgery?. N. Engl. J. Med. 2012. 366:2519-21.