Surgery in Native Valve Infective Endocarditis

In general, this tends to be a tricky subject. Add that to the fact that there are varying recommendations from different societies, it becomes difficult to figure out the who and when (I assume the surgeons will figure out the how). Here, we will look at timing of surgical intervention in left sided native infective endocarditis.

By far, it is generally recommended that those with left sided disease (i.e aortic and mitral valve endocarditis) be considered for surgery, since it physiologically makes sense they’ll have bad outcomes (i.e. ejection fraction takes into account the left sided of the heart…, plus there is the risk of emboli and such).

2015 European Society of Cardiology Guidelines in Infective Endocarditis:

The timing contrasts with the 2015 AHA/IDSA guidelines:

Here, early surgery is defined as being done during the initial hospitalization and prior to stopping antibiotics. The timing of surgery in these situations has been a subject of debate, as understandably there isn’t great data as to how to proceed.

While the indications for surgery are well recognized, other factors such as overall prognosis, severe sepsis and hemodynamic instability, and stroke (3), were factors that played a role in withholding surgery those who had an indication. Indeed, this prospective study found that those patients who underwent surgery tended to be younger, tended to have less co-morbidities, and worse left sided valvular disease.

Another analysis (4) from 2003 also found that those patients that tended to go to surgery were younger, have less co-morbidities, and had worse valvular problems from echocardiogram and/or intra-cardiac abscess. In an unadjusted analysis, these investigators found that those who underwent surgical repair for left sided native valve endocarditis had a significant difference in all cause mortality (16% in surgical group vs 33 in medical group, p-value <0.001. After propensity scores and cohort matching, those who underwent surgery still had a significant all cause mortality benefit at 6 months (see below):

In a subgroup analysis, those with severe heart failure demonstrated the greatest benefit in mortality reduction:

Unfortunately, the timing of surgery was not discussed. Indeed, their baseline timing was based on the day it was decided to operate or not, so it is difficult to interpret in terms of how it relates to mortality benefit and when to perform surgery.

Another prospective, multicenter study of infective endocarditis found that patients who had heart failure along with endocarditis had a significant higher mortality than those who did not have heart failure (30%, 95% CI 27.2-32.1% vs 13% 95% CI 11.8-14.4%, p-value <0.001). Further, those patients with IE and heart failure who underwent valve surgery had improved in-hospital mortality (see the 2 figures below, first is unadjusted results, second are propensity matching).

The one year mortality rate in both groups was 29.1% (95% CI 26-32%) for the surgical group vs 58.4% (95% CI 54-62.6%) in the medical group. This suggests that those who are very sick to begin with from IE would benefit from surgical intervention. Having said that, the answer to the question “when do you do surgery” is not answered.

To answer this question, a prospective, multinational cohort using the ICE-PCS database (6) was done to evaluate the impact on early surgery on in-hospital mortality. Early surgery was defined as occurring within the initial hospitalization for IE. To avoid the problems that arise from observational studies of this nature (seriously, in all studies, the patients who got surgery were younger, less sick, usually transferred patients with blown valves…), they used propensity score matching and multivariate regression analysis (aka magic). Here, a higher mortality benefit was found in the unadjusted univariate analysis and persisted after logistic regression and propensity matched analysis. Further, the benefit seem to also apply to those patients with perivalvular abscess, systemic emboli and staph aureus infection, but not heart failure patients.

Another older prospective cohort study (7) evaluated 5 year all cause mortality after discharge from a hospitalization for IE. Surgery was performed in the index hospitalization. After using a propensity model and propensity score matching, they found that there was an overall mortality benefit that seemed to result after roughly 40 days.

Multivariate analysis found that surgery was associated with survival in the matched cohort, compared to diabetes, presence of a line and perivalvular complications.

The Kaplan-Meyer curve is interesting, suggesting that mortality remains fairly high post-op, but those who make it may reap the benefits of the initial surgery (see later). Of course, all these studies vary in terms of the timing of surgery. By far, all of them seem to do the surgery within a few days or perhaps a week (as long as the index hospitalization is), which seem to correspond to the AHA/IDSA guidelines of “early surgery.”

The best study in terms of quality of data come from Korea (8), which was a prospective randomized trial evaluated early (within 48hrs of randomization) surgery vs standard of care (which could involve surgery if there was any significant decompensation). It involved left sided native IE with severe valve disease and vegs >10mm and excluded those with moderate to severe heart failure and heart block (??). Primary end point was composite of hospital death or embolic events within 6 weeks after randomization. One of the neat things about this study is that, since it was randomized, both groups were pretty similar (without fancy statistical magic!):

In terms of the primary outcome, at 6 weeks there was a benefit to surgery in the composite outcome (3% composite of death and embolic events vs  23%, HR .10, 95% CI 0.01 to 0.82).

Looking a bit closer, this seems to have been driven mostly by the rate of embolic phenomena. Indeed, the authors report that 6 weeks after randomization, the rate of embolism in the early surgery group was 0% vs 21% in the conventional-treatment group. Further, as seen above, at roughly ~14-15 weeks, the rate of death was similar in both groups, but the composite outcome was significantly different, suggesting that the rate of embolic events was the main driver in the primary outcome.

A meta-analysis found that early surgery favored both in-hospital and long-term mortality (9). However the definition of early surgery varied from within 7d of diagnosis up to 30 days or even during initial hospitalization, whatever that means.

A more recent prospective analysis using data from the INSTICNCT and ISAC trials evaluated the impact of timing in native left sided Staph Aureus endocarditis, with primary endpoint being all-cause mortality (7). They defined early valve surgery as occurring within 60 days of bacteremia. The all cause mortality at day 30 was 12% in the early surgery group vs 31% in the non-early surgery group and at day 90 it was 30% and 45% respectively (31% overall). IT should be noted, those who underwent surgery had more complications going into the surgery:

A regression model and a weighted Cox model did not find survival benefit in early surgery (again, described as it being within 60 days of diagnosis).

Even looking at those patients who underwent surgery within 14 days, there was no difference in outcomes when it comes to mortality. One thing the authors do note is that roughly 75% of patients who died after surgery did so in the first 60 days post-op, suggesting the high risk of death in the early phase post op.

SO this study suggests there is no mortality benefit for surgery in the first 2 months, but of course it is difficult to correct for the selection bias that occurs when doing these types of studies. Plus, it only involves one organism and the definition of “early valve surgery” is kind of ridiculous..

All in all, the immediate post-op risk seems to be fairly high, however making it through the initial post op period would mean that you have a lower morbidity from embolic events. The question of when to do surgery on left sided endocarditis patients (native), who have a big vegetation and have moderate to severe valve dysfunction is still up in the air, but most of the data suggests that, as long as it is safe, the earlier the better in terms of both short term mortality and long term morbidity.

References:

1. Habib, Gilbert, 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)].” Giornale Italiano Di Cardiologia (2006), vol. 17, no. 4, 2016, pp. 277-319.
2. Baddour, Larry M., 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, vol. 132, no. 15, 2015, pp. 1435-86.
3. Chu, Vivian H., et al. “Association Between Surgical Indications, Operative Risk, and Clinical Outcome in Infective Endocarditis: a Prospective Study From the International Collaboration On Endocarditis.” Circulation, vol. 131, no. 2, 2015, pp. 131-40.
4. Vikram, Holenarasipur R., et al. “Impact of Valve Surgery On 6-month Mortality in Adults With Complicated, Left-sided Native Valve Endocarditis: a Propensity Analysis.” JAMA, vol. 290, no. 24, 2003, pp. 3207-14.
5. Kiefer, Todd, et al. “Association Between Valvular Surgery and Mortality Among Patients With Infective Endocarditis Complicated By Heart Failure.” JAMA, vol. 306, no. 20, 2011, pp. 2239-47.
6. Lalani, Tahaniyat, et al. “Analysis of the Impact of Early Surgery On In-hospital Mortality of Native Valve Endocarditis: Use of Propensity Score and Instrumental Variable Methods to Adjust for Treatment-selection Bias.” Circulation, vol. 121, no. 8, 2010, pp. 1005-13.
7. Aksoy, Olcay, et al. “Early Surgery in Patients With Infective Endocarditis: a Propensity Score Analysis.” Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America, vol. 44, no. 3, 2007, pp. 364-72.
8. Kang, Duk-Hyun, et al. “Early Surgery Versus Conventional Treatment for Infective Endocarditis.” The New England Journal of Medicine, vol. 366, no. 26, 2012, pp. 2466-73.
9. Liang F, Song B, Liu R, Yang L, Tang H, Li Y. Optimal timing for early surgery in infective endocarditis: a meta-analysis. Interact CardioVasc Thorac Surg 2016;22:336–45.
10. Rieg, Siegbert, et al. “Investigating the Impact of Early Valve Surgery On Survival in Staphylococcus Aureus Infective Endocarditis Using a Marginal Structural Model Approach: Results of a Large, Prospectively Evaluated Cohort.” Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America, vol. 69, no. 3, 2019, pp. 487-494.