Michael Tzu Min , James , and Tom Kai Ming: Early or Delayed Surgery for Infective Endocarditis Complicated by Cerebral Embolism: A Meta-Analysis.

Introduction

Cerebral embolism complicates 15-30% of infective endocarditis, and is an indication for surgery alongside severe valvular regurgitation, heart failure and uncontrolled infection[1]. Early surgery is effective and advocated in infective endocarditis with large vegetations for primary prevention of embolic events in one randomised trial and international guidelines [1,2], but the optimal timing of surgery remains controversial in those with cerebral embolism, due to the sparse literature and absence of randomised studies. In this meta-analysis, outcomes of early or deferred infective endocarditis surgery with cerebral embolism was pooled and compared

Methods

PubMed, MEDLINE, Embase, Cochrane and Scopus databases from 1 January 1980 to 30 June 2016 were searched for original studies. We used the search terms “endocarditis” AND (“surgery” OR “operation”) AND (“stroke” OR “embolism” OR “cerebrovascular” OR “cerebral” OR “neurological”). Two authors (MTMW and TKMW) independently assessed searched articles for inclusion, using the Endnote X7.0.1 (Thomson Reuters 1988-2013) software to manage articles, and discrepancies resolved by consensus. Studies were included if patients had infective endocarditis with cerebral embolic complications for cardiac surgery, with outcomes of both early and late surgery arms reported.

Characteristics and outcomes from included studies were recorded using Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA, USA). Pooled odds ratios of outcomes by timing of surgery was calculated using the Review Manager 5.3 (Cochrane Collaboration, London, UK) program.

Results

The search yielded 2,423 papers, and after initial screening and exclusions, 23 full-texts were reviewed, with the final 6 studies involving 701 patients were included for analyses. Reasons of exclusions after initial screening include not reporting outcomes of both early or late surgery, and deferred group including both patients with delayed surgery or purely medical management, and having only intracranial bleed patients and case reports or reviews. Early surgery was defined as <7 days from diagnosis in 2 studies and <14 days in 4 studies. Table 1 lists the characteristics of the 6 included studies.

Figure 1 illustrates the pooled odds ratio of operative mortality. Rates and pooled odds ratio (95% confidence interval) of early versus late surgery set at 7 days were 13.5% vs 10.8%, 1.40 (0.61-3.02) in 2 studies; 14 days were 20.7% vs 13.0%, 1.95 (0.95-4.01) in 4 studies. Pooled odds ratio of all studies reporting long-term mortality was 2.95 (0.35-25.0), reported in 2 studies, both using 14 days as cutpoint.

In terms of neurological events, rates and pooled odds ratios of ischaemic stroke or transient ischaemic attack for early versus late surgery were 3.5% vs 2.0%, 1.22 (0.33-4.56) in 3 studies. For intracranial haemorrhage, these were 5.0% vs 2.2%, 1.55 (0.16-15.32) in 2 studies. These analyses are shown in Figure 2.

Discussion

The 2015 European Society of Cardiology (ESC) guidelines for infective endocarditis recommend “urgent” surgery, loosely defined as within a few days of diagnosis, for those with left-sided heart valve endocarditis with embolic event(s) [1]. It further describes surgery is recommended “without delay”, for those with silent emboli or transient emboli; in those with ischaemic stroke, surgery is “not contraindicated” unless severe neurological damage without timing recommendations; and with intracranial haemorrhage, generally be postponed to over 1 month later. All these recommendations however are based on small observational studies and/or expert consensus.

Our meta-analysis found no statistically significant differences for the main outcomes evaluated for early versus late surgery. In the current era when urgent early surgery is recommended including by the guidelines [1,2], our finding is reassuring that early surgery is safe. There still needs to be caution because numerically higher pooled adverse event rates (P>0.05), when surgery is performed very soon after cerebral embolism particular those with significant symptoms, at theoretical risk of neurological deterioration.

Beyond timing of surgery, there are a number of other approaches to try and reduce neurological complications in endocarditis patients[1]. Early diagnosis and initiation of antibiotic therapy is critical. Urgent surgery should be considered for those with high risk such as large vegetations for primary prevention of cerebral embolism [1,2]. Multidisciplinary heart team discussion and clinical judgement remains cornerstone to the management also.

This study has several limitations to highlight. There is no randomised data with all the studies being observational, and therefore significant differences in baseline characteristics exist and would affect the pooled results which were unadjusted. The numbers of patients were low for all studies, giving only a modest pooled sample power and inability to look at subgroups. The studies had wide heterogeneity from definitions of early and late surgery to being 7 or 14 days (and none used the 48 hours cutpoint of the randomised trial for primary embolic prevention as cutpoint), of outcomes like neurological events, of follow-up duration amongst others.

In conclusion, there were no significant differences in mortality and neurological outcomes between early and late surgery, which while confirms the safety of early surgery, there should still be a caution undertaking. Further studies especially larger and/or randomised trials are required to address this important clinical problem.

Table 1.

Author Year Study period Country Centre N Early surgery (days) Age (years) Male Prosthetic valve Operative mortality
Basic[3] 2013 June 2000-December 2006 28 64 58 <7 53.1 69.0% (40) 22.4% (13) 22.4% (13)
140 >7 57 67.9% (95) 22.9% (32) 12.1% (17)
Funakoshi[4] 2010 1990-2009 Japan 1 34 <14 5.8% (2)
27 >14 7.4% (2)
Garcia[5] 2013 1984-2009 Spain 7 43 <14 46.5% (20)
26 >14 38.5% (10)
Kim[6] 2011 1992-2007 Korea 1 34 <14 43.5 67.6% (23) 2.9% (1) 5.9% (2)
22 >14 49.0 63.6% (14) 27.3% (6) 0.0% (0)
Morita[7] 2015 July 2010-March 2013 Japan 82 105 <7 57 69.5% (73) 1.0% (1) 8.6% (9)
148 >7 62.5 66.2% (98) 1.4% (2) 9.5% (14)
Yoshioka[8] 2012 2005-2010 Japan 1 34 <14 64.2 61.8% (21) 17.7% (6) 17.7% (6)
30 >14 58.8 66.7% (20) 6.7% (2) 10.0% (3)

Figure 1

Pooled odds ratios of operative mortality for early versus delayed surgery for studies defining (a) 7 days and (b) 14 days as cutpoint.

icfj.2017.11.13-g001.jpg

Figure 2

Pooled odds ratios of neurological events for early versus delayed surgery for (a) ischaemic stroke or transient ischaemic attack, and (b) intracranial bleed.

icfj.2017.11.13-g002.jpg

Conflicts of Interests

The authors declare no conflicts of interest.

Acknowledgements

The authors state that they abide by the “Requirements for Ethical Publishing in Biomedical Journals” [9].

References

1. 

Habib G, Lancellotti P, Antunes MJ, Bongiorni MG, Casalta JP, Del Zotti F et al 2015; ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Eur Heart J 2015; 36: 3075–3128 10.1093/eurheartj/ehv319

2. 

Kang DH, Kim YJ, Kim SH, Sun BJ, Kim DH, Yun SC et al Early surgery versus conventional treatment for infective endocarditis. N Engl J Med 2012; 366: 2466–2466 10.1056/NEJMoa1112843

3. 

Barsic B, Dickerman S, Krajinovic V, Pappas P, Altclas J, Carosi G et al International Collaboration on Endocarditis–Prospective Cohort Study Investigators. Influence of the timing of cardiac surgery on the outcome of patients with infective endocarditis and stroke. Clin Infect Dis 2013; 56: 209–209 10.1093/cid/cis878

4. 

Funakoshi S, Kaji S, Yamamuro A, Tani T, Kinoshita M, Okada Y et al Impact of early surgery in the active phase on long-term outcomes in left-sided native valve infective endocarditis. J Thorac Cardiovasc Surg 2011; 142: 836–836 10.1016/j.jtcvs.2011.01.040

5. 

García-Cabrera E, Fernández-Hidalgo N, Almirante B, Ivanova-Georgieva R, Noureddine M, Plata A et al Neurological complications of infective endocarditis: risk factors, outcome, and impact of cardiac surgery: a multicenter observational study. Circulation 2013; 127: 2272–2284 10.1161/CIRCULATIONAHA.112.000813

6. 

Kim GS, Kim JB, Jung SH, Yun TJ, Choo SJ, Chung CH et al Surgical Management of Infective Endocarditis Complicated by Embolic Stroke: Early versus Delayed Surgery. Korean J Thorac Cardiovasc Surg 2011; 44: 332–332 10.5090/kjtcs.2011.44.5.332

7. 

Morita K, Sasabuchi Y, Matsui H, Fushimi K, Yasunaga H Outcomes after early or late timing of surgery for infective endocarditis with ischaemic stroke: a retrospective cohort study. Interact Cardiovasc Thorac Surg 2015; 21: 604–604 10.1093/icvts/ivv235

8. 

Yoshioka D, Sakaguchi T, Yamauchi T, Okazaki S, Miyagawa S, Nishi H al. Impact of early surgical treatment on postoperative neurologic outcome for active infective endocarditis complicated by cerebral infarction. Ann Thorac Surg 2012; 94: 489–95 10.1016/j.athoracsur.2012.04.027

9. 

Shewan LG, Coats AJS, Henein M Requirements for ethical publishing in biomedical journals. International Cardiovascular Forum Journal 2015; 2: 2 10.17987/icfj.v2i1.4



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