Early Surgery for Infective Endocarditis Decreases Risk of Embolization, Mortality

Abstract & Commentary

By Richard R. Watkins, MD, MS, FACP

Division of Infectious Diseases, Akron General Medical Center, Akron, OH; Associate Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH

Dr. Watkins reports no financial relationships relevant to this field of study.

This article originally appeared in the August 2012 issue of Infectious Disease Alert. It was edited by Stan Deresinski, MD, FACP, FIDSA, and peer reviewed by Timothy Jenkins, MD. Dr. Deresinski is Clinical Professor of Medicine, Stanford University, and Dr. Jenkins is Assistant Professor of Medicine, University of Colorado, Denver Health Medical Center. Dr. Deresinski does research for the National Institutes of Health, and is an advisory board member and consultant for Merck, and Dr. Jenkins reports no financial relationships relevant to this field of study.

Synopsis: In this randomized study, patients with left-sided infective endocarditis and large vegetations who underwent valve replacement surgery within 48 hours of randomization had lower rates of embolic events and death from any cause after 6 months compared to those who underwent surgery later.

Source: Kang D-Y, et al. Early Surgery versus Conventional Treatment for Infective Endocarditis. N Engl J Med 2012;366:2466-2473.

Infective endocarditis (IE) continues to be a serious illness with high morbidity and mortality despite modern therapies. Current guidelines from the American Heart Association state that the benefit from surgical intervention is greatest in the early phases of IE, when embolic rates are highest and other predictors of a complicated course are present.1 Kang and colleagues conducted a prospective, randomized, controlled trial in patients 18 years of age and older with left-sided, native-valve IE and a high risk of embolization. Eligible patients received a diagnosis of IE by the modified Duke criteria, had severe mitral or aortic valve disease and a vegetation ≥ 10 mm in diameter. All patients underwent transesophageal echocardiography and computed tomography of the brain and abdomen to evaluate for embolism. They were assigned in a 1:1 ratio to the early-surgery group (valve replacement within 48 hours after randomization) or the conventional treatment group (surgery performed only if complications developed during medical therapy or if symptoms persisted after completion of antibiotic therapy). Between September 2006 and March 2011, 37 patients were assigned to early surgery and 39 to conventional therapy. The primary end point was in-hospital death or clinical embolic events within 6 weeks of randomization. Secondary end points at 6 months of follow-up were death from any cause, embolic events, recurrence of IE, and hospitalization due to congestive heart failure (CHF).

The investigators found that the most common pathogens were viridans streptococci (30% of patients), other streptococci (in 30%), and Staphylococcus aureus (in 11%). There were no significant differences in antibiotic therapy between the two groups. The median time from randomization to surgery in the early-surgery group was 24 hours (range 7 to 45 hours). The primary end point of in-hospital death or embolic events within the first 6 weeks occurred in one patient (3%) in the early-surgery group, compared to 9 (23%) in the conventional-treatment group (hazard ratio, 0.10; 95% confidence interval 0.01 to 0.82; P=0.03). At 6 weeks after randomization, the rate of embolization in the early-surgery group was 0% compared to 21% in the conventional-treatment group (P=0.005). Among the 11 patients in the conventional-treatment group who were discharged without having surgery, 1 (3%) died suddenly, 7 (18%) had symptoms related to severe valve disease or recurrence of IE, and 3 (8%) had no symptoms or embolic events. At 6 months the rate of death from any cause, embolic events, recurrence of IE, or repeat hospitalization due to the development of CHF was 3% in the early-surgery group, compared to 28% in the conventional-treatment group (hazard ratio, 0.08; 95% confidence interval, 0.01 to 0.65; P=0.02). There was no significant difference between the groups in all-cause mortality at 6 months (3% and 5%, P=0.59).

There were several limitations to the study. One was the overall number of patients in the two groups was small. This was likely a consequence of the exclusion criteria chosen by the authors: patients with strokes, IE involving prosthetic valves, or aortic abscess. Another limitation was the low incidence of S. aureus IE, which was lower than previously reported.2 The rate of death within 30 days after surgery was low and the patients had a low operative risk. This implies that the results of the study may not be applicable to low-volume medical centers or to patients with a high operative risk. The study was conducted at two medical centers and the researchers did not analyze outcomes according to each participating center because of large differences in numbers of patients enrolled at each site. Follow-up imaging studies to detect subclinical embolic events were not done.

Commentary

The decision about when a patient should undergo surgical intervention for IE is often challenging. The current IE guidelines strongly recommend urgent surgery for patients with CHF due to valvular regurgitation.1 However, in patients with large vegetations and valve dysfunction but not CHF the guidance is less clear. The study by Kang and colleagues has provided valuable new data on this clinical conundrum. Their findings are very convincing to support the argument in favor of early surgery for patients with large vegetations and valvular dysfunction without overt CHF. As pointed out in an accompanying editorial, the benefits of timely intervention outweighed the additional risk of surgery in patients with active infection.3 Adequate debridement during surgery and optimal antibiotic selection based on culture data is also paramount to achieve successful outcomes.

It was surprising that S. aureus, including methicillin-resistant S. aureus (MRSA), was not a more common etiology of IE in the study. MRSA is highly pathogenic due to a multitude of virulence factors and is a frequent cause of embolic disease.4 It is unclear if the outcomes would have been different if more patients had S. aureus IE. Additional research to investigate this issue, especially in areas where MRSA is highly prevalent, is warranted.

The authors reported the time from randomization to surgery but not from diagnosis to surgery. Presumably these times were similar in most cases but this was not explicitly stated in the study. Moreover, the interval from onset of symptoms to surgery was not mentioned.

Despite its limitations, this study provides compelling evidence to support surgery in the first 48 hours for patients with left-sided IE, large vegetations and evidence of valvular dysfunction. IE is a perilous condition with a high risk of embolic events. The study by Kang and colleagues is important and will hopefully lead to improved clinical outcomes for patients. Future studies to replicate these data, especially with larger numbers of participants and high risk patients, are necessary to further elucidate the optimal timing of surgery in IE.

References

1. 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.

2. Kiefer T, et al. Association between valvular surgery and mortality among patients with infective endocarditis complicated by heart failure. JAMA 2011;306:2239-47.

3. Gordon SM, et al. Native-valve infective endocarditis- when does it require surgery? N Engl J Med 2012;366:2519-20.

4. Watkins RR, et al. Current concepts on the virulence mechanisms of methicillin-resistant Staphylococcus aureus. J Med Microbiol 2012 Jun 28. [Epub ahead of print].