The annual incidence of infective endocarditis (IE) is estimated to be 3 to 9 cases per 100,000 persons in developed countries [1-2]. Neurologic complications are the most severe and frequent extracardiac complications of IE, affecting 15-20% of patients [3-4]. They consist of 1) ischemic infarction secondary to septic emboli from the valvular vegetation, which can eventually undergo hemorrhagic transformation; 2) focal vasculitis/cerebritis from septic emboli obstructing the vascular lumen, which can then develop into brain abscess or meningoencephalitis; 3) mycotic aneurysm secondary to inflammation from septic emboli penetrating the vessel wall . Amongst these complications, stroke is the most common and is the presenting feature in 50-75% of patients . To date, an ongoing debate amongst physicians is the appropriateness of anticoagulation in patients with IE and how to balance the risk of thromboembolism against that of hemorrhagic transformation of stroke.
Specific risk factors have been associated with increased risk of symptomatic embolic events. Embolic risk is especially high within the first 2 weeks after diagnosis, decreasing in frequency after initiation of antibiotics . Size, location and mobility of vegetations are key predictors; in fact, surgery may be indicated for prevention of embolism with involvement of anterior mitral leaflet, vegetation size >10mm, or increasing size despite appropriate antibiotics [5,8]. Additional risk factors for embolism in IE include advanced age and S. aureus infection. Importantly, S. aureus prosthetic valve endocarditis is known to be associated with higher overall mortality and severe neurologic complications such as hemorrhagic stroke [3,9-10]. Mechanisms for intracranial hemorrhage (ICH) in patients with IE include hemorrhagic transformation (HT) of ischemic infarct, rupture of mycotic aneurysms, or erosion of septic arteritic vessels .
Currently, evidence regarding anticoagulants primarily stems from observational studies. One of the arguments against anticoagulation in IE is the fear of early ICH and HT of ischemic stroke. In Tornos et al.’s retrospective observational series of 56 patients with native and prosthetic S. aureus IE, mortality was higher in prosthetic valve IE than in native valve IE (p=.02; odds ration [OR], 4.23; 95% confidence interval [CI], 1.15-16.25) . The authors inferred that part of this difference stemmed from the deleterious effect of anticoagulation leading to lethal neurologic damage as 90% of patients with prosthetic valve IE due to S. aureus were receiving oral anticoagulant treatment on admission (vs. no patient with native valve IE due to S. aureus was receiving such treatment). Meanwhile, in Heiro et al.’s retrospective study, a sub-analysis of 32 patients with S. aureus IE showed that 57% of patients receiving anticoagulant therapy died within 3 months of admission vs. 20% of those not receiving anticoagulant therapy, though the difference was not statistically significant (p=0.1) . Garcia-Cabrera et al. conducted a retrospective analysis of 1,345 cases of left-sided IE, and likewise found that hemorrhagic complications were significantly associated with anticoagulant therapy that was primarily used in patients with mechanical valves (hazard ration [HR] 2.71, 95% CI 1.54-4.76, p=0.001) . On this basis, these authors have recommended stopping anticoagulants as soon as diagnosis of IE is suspected, at least until past the septic phase of the disease. Despite these reported associations of poor outcome in S. aureus IE and detrimental effect of anticoagulant therapy in these patients, these results arose from nonrandomized retrospective studies without matched cohorts. Moreover, Tornos et al.’s study was primarily designed to compare native valve with prosthetic valve IE patients, and the sample size of those receiving anticoagulation was small (19 out of 56) . Similarly, Heiro et al.’s study was of limited statistical power, as only 2 of the 4 patients with lethal S. aureus IE actually died of hemorrhagic conditions while taking anticoagulant therapy.
On the opposing end, more recent prospective studies show no significant association between anticoagulation and increased risk of hemorrhagic complications, and that ICH due to anticoagulation after IE-related stroke is overestimated. Rasmussen et al. conducted a prospective cohort study of 175 S. auerus IE patients, of which 70 patients (40%, 95% CI 33-47%) experienced major cerebral events during the course of the disease . Stroke was the most common complication (34%, 95% CI 27-41%), but the incidence of cerebral hemorrhage was low (3%, 95% CI 0.5-6%). None of the patients who experienced cerebral hemorrhage were receiving anticoagulant treatment. In fact, Rasmussen et al. found that patients receiving anticoagulation were less likely to have experienced a major cerebral event at time of admission compared to those not receiving such treatment (15% vs 37%, p=0.009). The indication for anticoagulation for the majority of patients in this study was prosthetic heart valves. Anticoagulation at the time of admission was associated with a significant reduction in the number of major cerebral events in patients with native valve IE (0 vs. 39%, p=0.008); however, this was not evident in those with prosthetic valve IE. In-hospital mortality rate was 23% (95% CI 17-29%) with no significant difference between patients with or without anticoagulant therapy.
An added complication to the picture is the decision for cardiac surgery in patients with IE who suffer a neurologic event. Except for clinically severe ICH, neurologic complications are not a contraindication for surgical treatment . The decision to perform cardiopulmonary bypass remains controversial, as the surgery can cause/aggravate cerebral damage in several ways, such as ICH related to heparinization during the procedure, and possible hemodynamic worsening of the ischemic infarction (e.g. additional embolism, hypoperfusion) [5,15]. The timing of the surgery is also hotly debated, and evidence supporting surgical intervention is of limited quality and primarily based on observational studies. However, when needed, cardiac surgery can be performed promptly after a silent cerebral embolism or transient ischemic attack, but must be postponed for at least 1 month following ICH .
Despite controversy over anticoagulant therapy, recommendations regarding antiplatelet therapy are more clear-cut: antiplatelets are not recommended for patients with IE. In a double-blind, placebo-controlled trial comparing aspirin 325mg with placebo for 4 weeks in 115 IE patients, there was no significant decrease in the incidence of embolic events (OR 1.62, 95% CI 0.68-3.86) . In fact, there was a trend toward more bleeding in the aspirin group (OR 1.92, 95% CI 0.76-4.86); and aspirin had no effect on vegetation size. While there are conflicting findings from observation studies regarding the use of chronic antiplatelet treatment before IE, in terms risks of death and embolic events, current available evidence suggests that antiplatelet therapy is not indicated in IE [17-19]. Patients on antiplatelet therapy for other indications may continue taking it, in the absence of major bleeding.
So where does this leave us? According to the most recent European Society of Cardiology guidelines, there is no indication to start anticoagulation in patients with IE . For those already receiving anticoagulant therapy, and in which IE is complicated by ischemic or non-hemorrhagic stroke, the oral anticoagulant agent should be replaced by unfractionated heparin for 2 weeks. For those with ICH complication, all anticoagulation should be stopped, except for those with prosthetic valve IE in which case the recommendation is to reinitiate unfractionated heparin “as soon as possible” (no specified time-frame given in guidelines). Critically, the European Society of Cardiology guidelines acknowledge the low level of evidence supporting these recommendations.
Anticoagulation is undoubtedly a double-edged sword. Whenever cerebrovascular complications of IE are suspected, there should be low threshold to perform diagnostic brain imaging to rule out cerebral hemorrhage, which would definitively justify discontinuation of anticoagulation and likely postpone planned cardiac surgery. Repeat echocardiography and neuroimaging play an important role in management of IE patients. At this time, the lack of robust information on anticoagulant therapy in IE stresses the need for more large randomized controlled trials.
Dr. Shannon Chiu is a 2nd year resident at NYU Langone Medical Center
Peer Reviewed by Albert Jung, MD, Internal Medicine, NYU Langone Medical Center
Image courtesy of Wikimedia Commons
- Correa de Sa DD, Tleyjeh IM, Anavekar NS, et al.; Epidemiological trends of infective endocarditis: a population-based study in Olmsted County, Minnesota. Mayo Clin Proc. 2010;85:422-426. http://www.mayoclinicproceedings.org/article/S0025-6196%2811%2960327-3/fulltext
- Duval X, Delahaye F, Alla F, et al.; Temporal trends in infective endocarditis in the context of prophylaxis guideline modifications: three successive population-based surveys. J Am Coll Cardiol. 2012;59:1968-1976. http://www.sciencedirect.com/science/article/pii/S0735109712009849
- Thuny F, Avierinos JF, Tribouilloy C, et al.; Impact of cerebrovascular complications on mortality and neurologic outcome during infective endocarditis: a prospective multicentre study. Eur Heart J. 2007;28:1155-1161. http://eurheartj.oxfordjournals.org/content/28/9/1155.long
- Sonneville R, Mirabel M, Hajage D, et al.; Neurologic complications and outcomes of infective endocarditis in critically ill patients: the ENDOcardite en REAnimation prospective multicenter study. Crit Care Med. 2011;39:1474-1481. http://journals.lww.com/ccmjournal/Abstract/2011/06000/Neurologic_complications_and_outcomes_of_infective.35.aspx
- Ferro JM, Fonesca C. Infective endocarditis. Handb Clin Neurol, Neurologic Aspects of Systemic Disease Part I. 2014;119:75-91. http://www.sciencedirect.com/science/article/pii/B9780702040863000072
- Sila C. Anticoagulation should not be used in most patients with stroke with infective endocarditis. Stroke. 2011;42:1797-1798. stroke.ahajournals.org/content/42/6/1797.full.pdf
- Snygg-Martin U, Gustafsson L, Rosengren L, et al.; Cerebrovascular complications in patients with left-sided infective endocarditis are common: a prospective study using magnetic resonance imaging and neurochemical brain damage markers. Clin Infect Dis. 2008;47:23-30. http://cid.oxfordjournals.org/content/47/1/23.long
- Habib G, Hoen B, Tornos P, et al.; The task force on the prevention, diagnosis, and treatment of infective endocarditis of the European Society of Cardiology (ESC). Eur Heart J. 2009;30:2369-2413. http://eurheartj.oxfordjournals.org/content/ehj/30/19/2369.full.pdf
- Heiro M, Nikoskelainen J, Engblom E, et al.; Neurologic manifestations of infective endocarditis: A 17-Year Experience in a Teaching Hospital in Finland. Arch Intern Med. 2000;160:2781-2787. http://archinte.jamanetwork.com/article.aspx?articleid=485459
- Di Salvo G, Habib G, Pergola V, et al.; Echocardiography predicts embolic events in infective endocarditis. J Am Coll Cardiol. 2001;37:1069-1076. http://www.sciencedirect.com/science/article/pii/S0735109700012067
- Molina CA, Selim MH. Anticoagulation in patients with stroke with infective endocarditis: the sword of Damocles. Stroke. 2011;42:1799-1800. http://stroke.ahajournals.org/content/42/6/1799.full.pdf
- Tornos P, Almirante B, Mirabet S, et al.; Infective endocarditis due to Staphylococcus aureus: deleterious effect of anticoagulant therapy. Arch Intern Med. 1999;159:473-475. http://archinte.jamanetwork.com/article.aspx?articleid=414876
- Garcia-Cabrera E, Fernandez-Hidalgo N, Almirante B, et al.; Neurological complications of infective endocarditis: risk factors, outcome, and impact of cardiac surgery: a multicenter observational study. Circulation. 2013;127(23):2272-84. http://circ.ahajournals.org/content/127/23/2272.long
- Rasmussen RV, Snygg-Martin U, Olaison L, et al.; Major cerebral events in Staphylococcus aureus infective endocarditis: is anticoagulant therapy safe? Cardiology. 2009;114:284-291. http://www.karger.com/Article/FullText/235579
- Goldstein LB, Husseini NE. Neurology and cardiology: points of contact. Rev Esp Cardiol. 2011;64(4):319-27. http://www.sciencedirect.com/science/article/pii/S188558571100154X
- Chan KL, Dumesnil JG, Cujec B, et al.; A randomized trial of aspirin on the risk of embolic events in patients with infective endocarditis. J Am Coll Cardiol. 2003;42:775-780. http://content.onlinejacc.org/article.aspx?articleid=1132570
- Anavekar NS, Tleyjeh IM, Anavekar NS, et al.; Impact of prior antiplatelet therapy on risk of embolism in infective endocarditis. Clin Infect Dis. 2007;44:1180-1186. http://cid.oxfordjournals.org/content/44/9/1180.long
- Pepin J, Tremblay V, Bechard D, et al.; Chronic antiplatelet therapy and mortality among patients with infective endocarditis. Clin Microbiol Infect. 2009;15:193-199. http://onlinelibrary.wiley.com/doi/10.1111/j.1469-0691.2008.02665.x/full
- Chan KL, Tam J, Dumesnil JG, et al.; Effect of long-term aspirin use on embolic events in infective endocarditis. Clin Infect Dis. 2008;46:37-41. http://cid.oxfordjournals.org/content/46/1/37.long