Antithrombotic therapy in patients with infective endocarditis

INTRODUCTION — Management of antithrombotic therapy (anticoagulant and antiplatelet agents) in patients with infective endocarditis (IE) is challenging given the competing risks of embolism and intracerebral hemorrhage in this condition and limited evidence on the effects of therapy. Anticoagulant and antiplatelet therapy have not been shown to reduce the risk of embolism in IE. However, many patients with IE have indications for antithrombotic therapy, particularly patients with mechanical prosthetic valves. In such patients, the potential risks and benefits of antithrombotic therapy must be carefully weighed.

The use of anticoagulants and antiplatelet agents in patients with IE will be reviewed here. The treatment and complications of IE are presented separately.

●(See "Right-sided native valve infective endocarditis".)

●(See "Antimicrobial therapy of left-sided native valve endocarditis".)

●(See "Antimicrobial therapy of prosthetic valve endocarditis".)

●(See "Surgery for left-sided native valve infective endocarditis".)

●(See "Surgery for prosthetic valve endocarditis".)

●(See "Complications and outcome of infective endocarditis".)

The importance of anticoagulation in patients with noninfective thrombotic endocarditis (also called marantic endocarditis, Libman-Sacks endocarditis, verrucous endocarditis), typically associated with cancer, is also discussed separately. (See "Nonbacterial thrombotic endocarditis", section on 'Treatment'.)

MANAGEMENT APPROACH — Antithrombotic therapy (anticoagulant or antiplatelet therapy) is not indicated to reduce the risk of thromboembolic complications of IE. However, patients with IE frequently have other/separate indications for anticoagulant or antiplatelet therapy and such therapy is appropriate if the potential benefit of antithrombotic therapy outweighs the potential risk. Data to guide the use of anticoagulants and antiplatelet therapies in the setting of IE are limited. Thus, recommendations are based largely on observational data and expert opinion. Since there are competing risks of thromboembolism and bleeding in every patient with IE, we individualize therapy based on a multidisciplinary approach to patient and disease factors. When weighing the potential risks and benefits of antithrombotic therapy in patients with IE, the magnitude of risk as well as the duration of the period of risk should be considered.

The management approach described here is largely consistent with the 2015 American Heart Association (AHA) IE scientific statement, the 2015 European Society of Cardiology (ESC) IE guidelines, and the 2020 American College of Cardiology (ACC)/AHA valve guidelines, (as well as the 2021 ESC valve guidelines, which refer to the 2015 ESC IE guidelines) [1-5].

Clinical settings

Patients without other indications for antithrombotic therapy — In patients with IE without a separate indication for anticoagulation or antiplatelet therapy, initiation of anticoagulant or antiplatelet therapy is not indicated [1-4]. The available data do not demonstrate a convincing benefit for antithrombotic therapy in preventing embolic complications in patients with IE and suggest possible increased risk of bleeding complications. (See 'Effect of antithrombotic therapy' below.)

Patients with other indications for antithrombotic therapy — In patients with IE with a separate indication for antithrombotic therapy, the risk of withholding antithrombotic therapy is weighed against the risk of antithrombotic therapy (particularly the risk of intracerebral hemorrhage).

Conditions commonly treated with anticoagulants

Prosthetic valves — Patients with strong indications for continuing antithrombotic therapy in the setting of IE include those with mechanical prosthetic valves. The risk of thromboembolism and valve thrombosis in patients with prosthetic valves is summarized here and discussed in detail separately. (See "Mechanical prosthetic valve thrombosis or obstruction: Clinical manifestations and diagnosis" and "Antithrombotic therapy for mechanical heart valves".)

Patients with prosthetic valves are at risk for thromboembolism as well as for valve obstruction from valve thrombosis.

●Thromboembolism – The risk of this complication is highest during the first 30 to 90 days after valve implantation in patients with bioprosthetic or mechanical valves. After that early period, the risk is higher in patients with mechanical valves if not treated with anticoagulation (vitamin K antagonist [VKA] or heparin). In patients with mechanical aortic valves who are treated with VKA therapy (eg, warfarin), the long-term frequency of systemic embolization, predominantly cerebrovascular events, is approximately 0.7 to 1.0 percent per year (which is similar to the risk of embolization in patients with bioprosthetic valves without anticoagulant therapy). The risk of systemic embolization is approximately twice as high with a mitral valve. By comparison, the risk of embolization is 2.2 percent per year with aspirin and 4.0 percent per year with no anticoagulation in patients with mechanical valves (data not specific for valve position). The risk of thromboembolism during the first 10 to 30 days after valve replacement is approximately 15 to 25 times higher than after the first 90 days.

●Prosthetic valve thrombosis may be asymptomatic but can progress to acute or chronic valvular obstruction with mortality rates greater than 35 percent in those who become critically ill with acute obstruction. The reported annual incidence of prosthetic valve thrombosis ranges from 0.03 to 5.7 percent with higher rates observed in patients with mechanical valves treated with subtherapeutic anticoagulation. The risk of valve obstruction from thrombosis is also higher in the presence of a mitral valve. (See "Mechanical prosthetic valve thrombosis or obstruction: Clinical manifestations and diagnosis".)

Patients with acute valve thrombosis and/or large vegetations may require emergency surgical valve replacement or surgical removal of the thrombus though some patients (eg, those who are more stable and have smaller thrombi) may be treated by thrombolysis or anticoagulation. Management is discussed in detail separately (see "Bioprosthetic valve thrombosis, thromboembolism, and obstruction: Management"). However, thrombolysis is contraindicated in patients with IE who have a stroke given the risk of hemorrhagic transformation or worsening intracerebral hemorrhage. (See 'Ischemic stroke' below.)

We recommend anticoagulation in patients with mechanical valves based upon moderate quality evidence supporting long-term anticoagulation (with VKA) to reduce thromboembolism and valve thrombosis. Limited evidence is available comparing various regimens for bridging with unfractionated heparin or low molecular weight heparin until patients are stable on vitamin K anticoagulant therapy. In the early treatment of patients presenting with IE, VKA is replaced with unfractionated heparin or low molecular weight heparin as discussed below. (See "Antithrombotic therapy for mechanical heart valves" and 'Management of antithrombotic therapy if continued' below.)

Combined long-term aspirin and VKA therapy reduces risk of thromboembolism but increases risk of major bleeding compared with anticoagulation alone in patients with mechanical valves (see "Antithrombotic therapy for mechanical heart valves", section on 'Selective use of aspirin'). Since patients presenting with acute IE may be at increased risk for major bleeding, we generally avoid aspirin use and continue anticoagulant therapy alone in the setting of acute IE in the absence of other indications for antiplatelet therapy.

The risk of thromboembolism is increased early after bioprosthetic as well as mechanical valve replacement, though there is limited evidence on the efficacy of anticoagulant therapy early after bioprosthetic valve replacement. We suggest antithrombotic therapy early after bioprosthetic valve replacement, though recommendations vary among experts. (See "Antithrombotic therapy for surgical bioprosthetic valves and surgical valve repair", section on 'Intermediate- and long-term antithrombotic therapy'.)

Atrial fibrillation — Patients with paroxysmal, persistent, or permanent atrial fibrillation are at risk for embolization of atrial thrombi. The magnitude of this risk is evaluated using the CHA₂DS₂-VASc score (table 1) (calculator 1). Antithrombotic therapy is recommended when the benefits outweigh the risk. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'.)

As illustrated by the following recommendations, we generally continue anticoagulation in patients with atrial fibrillation with IE with strong indications for anticoagulation but generally defer anticoagulation in patients with weaker indications for anticoagulation since patients with IE are likely at increased risk for major bleeding:

●Anticoagulant therapy (rather than antiplatelet therapy) is recommended in patients with atrial fibrillation with IE with a CHA₂DS₂-VASc score (table 1) (calculator 1) of 2 or greater.

●Anticoagulation is recommended in patients with atrial fibrillation with mitral stenosis with IE regardless of the CHA₂DS₂-VASc score. (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.)

In the early treatment of patients presenting with IE, direct oral anticoagulant (DOAC) or VKA is replaced with unfractionated heparin or low molecular weight heparin as discussed below. (See 'Management of antithrombotic therapy if continued' below.)

●In patients with atrial fibrillation without IE with a CHA₂DS₂-VASc score of 1, experts have differing approaches, ranging from suggesting no antithrombotic therapy to suggesting anticoagulation. However, since patients with acute IE are at increased risk of major bleeding, we suggest aspirin or no antithrombotic therapy (in preference to anticoagulation) for patients presenting with acute IE who have a CHA₂DS₂-VASc score of 1.

Venous thromboembolism — Adults hospitalized for an acute medical illness are at risk for venous thromboembolic disease (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE). Although prophylactic anticoagulation is often warranted in this population, the risk of VTE must be balanced against the risk of bleeding complications, including intracerebral hemorrhage, particularly in those who already have ischemic stroke and are thus at risk for hemorrhagic transformation. Given this risk, for hospitalized patients with IE with limited mobility, we suggest mechanical thromboprophylaxis (eg, intermittent pneumatic compression). (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)

For patients with IE and recent DVT and/or PE, the risk of VTE complications with withholding anticoagulation is balanced against the risk of bleeding complications with anticoagulation. For patients with IE without evidence of stroke or a condition posing a high risk of bleeding (such as acute Staphylococcus aureus endocarditis), standard recommendations for anticoagulation for DVT and/or PE are applicable. (See "Venous thromboembolism: Anticoagulation after initial management" and "Venous thromboembolism: Initiation of anticoagulation" and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults" and "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity".)

Conditions commonly treated with antiplatelet therapy

Coronary heart disease — The impact of IE on the benefits and risks of antiplatelet therapy for secondary prevention in patients with coronary artery disease is not known. Antiplatelet therapy for patients with coronary artery disease and IE should be governed by the applicable recommendations for coronary artery disease, including specific recommendations for patients who have undergone coronary artery stenting. This includes continuing aspirin indefinitely in all patients with coronary stents, in addition to time-limited dual antiplatelet therapy. The role of antiplatelet therapy in patients with coronary artery disease is discussed separately. (See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy" and "Acute ST-elevation myocardial infarction: Antiplatelet therapy" and "Long-term antiplatelet therapy after coronary artery stenting in stable patients" and "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

Secondary prevention of ischemic stroke — Antiplatelet therapy is used for both the management of acute ischemic stroke and for the secondary prevention of noncardioembolic ischemic stroke. However, there are few data to guide decisions about the initiation or continuation of antiplatelet therapy for secondary stroke prevention in patients who develop IE. Given the increased risk of hemorrhagic stroke in acute IE, we generally suspend antiplatelet therapy during treatment of IE. However, in the absence of bleeding complications, it is reasonable to continue antiplatelet therapy in acute IE for patients deemed to be at particularly high risk of recurrent noncardioembolic ischemic stroke because of factors such as recent transient ischemic attack (TIA) or high-grade stenosis of an extracranial or intracranial large artery.

Primary prevention of cardiovascular disease and cancer — Aspirin use modestly decreases the risk of nonfatal myocardial infarction and possibly decreases long-term colorectal cancer incidence, but increases the risk of major bleeding in adults without established cardiovascular disease and with average cancer risk. Since patients presenting with acute IE may be at increased risk for major bleeding, we generally suspend aspirin use for primary prevention during treatment of IE. (See "Aspirin in the primary prevention of cardiovascular disease and cancer".)

Management of antithrombotic therapy if continued — For patients with IE in whom the benefit of antithrombotic therapy (anticoagulant or antiplatelet therapy) is judged to outweigh the risk, we continue antithrombotic therapy after reviewing the echocardiogram and excluding contraindications such as an intracerebral hemorrhage or ischemic stroke by imaging. In patients at high risk of cardioembolic stroke other than IE alone (eg, a patient with a mechanical prosthetic valve, particularly if high-risk features are present), cautious anticoagulation may be continued if a small ischemic stroke is identified, although this recommendation is controversial. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".)

In patients with IE in whom a decision is made to continue anticoagulant therapy (eg, for a mechanical valve), we generally replace DOAC or VKA therapy (eg, warfarin) with unfractionated heparin or low molecular weight heparin therapy at the time of presentation while stability and potential need for an invasive procedure is assessed [6]. The switch is made so that anticoagulation can be quickly reversed should an indication for an invasive procedure develop or should a contraindication to anticoagulation arise (eg, a stroke or a bleeding complication). We generally initiate unfractionated heparin without a bolus to reduce the risk of bleeding. Patients treated with unfractionated or low molecular weight heparin should have a baseline platelet count obtained before heparin is started, and every two or three days from day four until the heparin is stopped [7]. Those with a drop in platelet count should be evaluated for heparin-induced thrombocytopenia. Patients treated with unfractionated heparin should receive careful monitoring of the activated partial thromboplastin time and strict avoidance of overanticoagulation. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)

Antithrombotic therapy should be discontinued when the potential risks of continuing antithrombotic therapy outweigh the potential benefits. Thus, in the setting of IE, antithrombotic therapy (antiplatelet and anticoagulant agents) should be immediately discontinued in all patients with serious or life-threatening bleeding (including intracerebral hemorrhage) and in most patients with ischemic stroke. In patients with serious or life-threatening bleeding, anticoagulation should also be reversed. Recommendations for reversal of anticoagulation differ in patients with and without mechanical prosthetic valves, given the risks of valve thrombosis and valve thromboembolism in patients with mechanical valves. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Treatment of bleeding' and "Anticoagulation for prosthetic heart valves: Management of bleeding and invasive procedures", section on 'Management of bleeding'.)

Management of cerebral complications

Ischemic stroke — In most patients with IE on anticoagulation who develop an acute ischemic stroke, we suggest discontinuing anticoagulant therapy for at least two weeks due to the risk of hemorrhagic transformation. In addition, we suggest not starting aspirin or other antiplatelet agents for patients with IE who have an acute ischemic stroke or TIA. These recommendations are consistent with the 2015 AHA scientific statement on IE [1]. The optimal length of time for discontinuation of anticoagulation is unknown and is based on limited evidence [1]. An exception applies to patients judged to have high risk of cardioembolic stroke (above the general risk of stroke associated with IE; eg, a patient with a mechanical valve with high-risk features) in whom cautious anticoagulation may be continued if the ischemic stroke is small, although this recommendation is controversial. This exception is not included in the 2015 AHA IE scientific statement. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".)

If there is a compelling need to reinstitute anticoagulant therapy during the first two weeks following the onset of stroke (eg, presence of a mechanical valve, particularly with high-risk features), serial brain imaging with computed tomography or magnetic resonance imaging should be performed to exclude hemorrhagic transformation or intraparenchymal hemorrhage [8].

Thrombolytic therapy is generally contraindicated in patients with IE and stroke [2,9]. A study based upon data from the Nationwide Inpatient Sample found high rates of post-thrombolytic intracerebral hemorrhage (20 versus 6.5 percent) and low rates of favorable outcomes (10 versus 38 percent) in patients with IE with ischemic stroke receiving intravenous thrombolytic therapy compared with patients with ischemic stroke without IE [9,10].

Intracerebral hemorrhage — All anticoagulant and antiplatelet agents should be immediately discontinued for at least two weeks in patients with intracerebral hemorrhage, including hemorrhagic stroke or hemorrhagic transformation of an embolic stroke. Management of intracerebral hemorrhage is discussed separately. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".)

In patients who develop an intracerebral hemorrhage while anticoagulated, anticoagulation should also be reversed. For those who have been taking warfarin or other VKA, reversal strategies depend upon the severity of the bleeding and the degree of anticoagulation. Rapid reversal of warfarin can be achieved using a four-factor prothrombin complex concentrate or fresh frozen plasma; longer-term reversal of warfarin (eg, for several days) is maintained by administering vitamin K. Reversal of anticoagulation with DOAC in this setting is discussed separately. (See "Reversal of anticoagulation in intracranial hemorrhage".)

In patients treated with a VKA for a mechanical prosthetic valve, reversal of anticoagulation should be undertaken with care to avoid risk of precipitating valve thrombosis. Reversal of anticoagulation for major bleeding (including intracerebral hemorrhage) in patients with prosthetic valves is discussed separately. (See "Anticoagulation for prosthetic heart valves: Management of bleeding and invasive procedures", section on 'Management of overanticoagulation without bleeding'.)

Early reinitiation of anticoagulation is favored, particularly for patients with a risk of thromboembolic complications (eg, those with a mechanical valve). As noted in the 2015 European Society of Cardiology IE guidelines, in patients with intracerebral hemorrhage and a mechanical valve, unfractionated or low molecular weight heparin should be reinitiated as soon as deemed prudent following multidisciplinary discussion [2].

Role of valve surgery — Patients with IE should be evaluated for development of indications for valve surgery [1,2]. We suggest early surgery in patients with IE with recurrent embolic events despite antibiotic therapy if they have standard indications for surgical treatment such as heart failure (HF) [4,5]. (See "Surgery for left-sided native valve infective endocarditis" and "Surgery for prosthetic valve endocarditis".)

The approach to surgical intervention for IE in the setting of recent embolic stroke is discussed separately. (See "Surgery for left-sided native valve infective endocarditis", section on 'Surgical indications'.)

EVIDENCE — Limited evidence is available to guide management of antithrombotic therapy in patients with IE. Interest in a potential role for antithrombotic therapy in IE is motivated by interest in reducing the substantial risk of embolic complications of IE. However, patients with IE are also at risk for bleeding complications, including intracerebral hemorrhage. The available limited data do not establish a benefit from anticoagulant or antiplatelet therapy in reducing the risk of embolic complications in patients with IE and the safety of such therapy is uncertain.

Risk of embolism in IE

Estimates of risk — Patients with IE are at high risk for embolic events, including embolic stroke. Approximately 35 percent of patients with IE have symptomatic cerebrovascular complications and as many as 80 percent of patients have evidence of stroke on imaging. Although less common than cerebral infarction, emboli can also cause myocardial infarction, septic cranial arteritis, mycotic aneurysms, and brain abscesses; right-sided emboli can cause lung abscesses. These are discussed separately. (See "Complications and outcome of infective endocarditis", section on 'Neurologic complications' and "Complications and outcome of infective endocarditis", section on 'Metastatic infection'.)

Risk factors — Many patient, disease, and therapeutic factors affect the risk of embolization in patients with IE. These are summarized here and discussed in detail separately. (See "Complications and outcome of infective endocarditis".)

●Size of vegetation – Larger vegetations are more likely to embolize; vegetations >10 mm are especially concerning. Vegetations that are visible on both transthoracic and transesophageal echocardiography (TEE) are more likely to embolize than those seen only on TEE. (See "Role of echocardiography in infective endocarditis", section on 'Prognostic markers' and "Complications and outcome of infective endocarditis", section on 'Risk factors'.)

●Location of vegetation – The risk of cerebral embolism is highest from mitral valve lesions, especially those on the anterior mitral leaflet. Most systemic emboli arise from the mitral or aortic valve (though they can rarely arise from a tricuspid valve vegetation with passage to the left heart via a patent foramen ovale). Right-sided vegetations frequently embolize to the lung with subsequent abscess formation. (See "Complications and outcome of infective endocarditis", section on 'Risk factors'.)

●Organism – The infectious organism may also influence the risk of septic emboli. Staphylococcus aureus endocarditis is associated with a higher risk of embolization than other bacterial organisms, with such events observed in 45 percent of patients with Staphylococcus aureus IE in one series. [11]. Data are conflicting as to whether group D streptococci (Streptococcus bovis/Streptococcus equinus) are associated with an increased risk of embolic events. Candida endocarditis is also associated with a higher risk of embolization, a probable reflection of larger vegetations with this organism. (See "Overview of Candida infections", section on 'Endocarditis' and "Clinical manifestations of Staphylococcus aureus infection in adults", section on 'Infective endocarditis' and "Infections due to Streptococcus bovis/Streptococcus equinus complex (SBSEC; formerly group D streptococci)" and "Infections due to Streptococcus bovis/Streptococcus equinus complex (SBSEC; formerly group D streptococci)", section on 'Bacteremia and endocarditis' and "Complications and outcome of infective endocarditis", section on 'Risk factors' and "Staphylococcus aureus bacteremia in children: Epidemiology and clinical features", section on 'Infective endocarditis'.)

●Antibiotic treatment – The risk of embolism markedly decreases in the weeks following initiation of effective antibiotic therapy. As an example, in a cohort study of 1437 patients with left-sided IE, the incidence of stroke fell from 4.8/1000 patient days in the first week of therapy to 1.7/1000 in the second week to <0.2/1000 in the fifth week [12]. (See "Complications and outcome of infective endocarditis", section on 'Effect of antibiotic therapy'.)

●Coexistent conditions – Patients with IE frequently have coexistent conditions that pose a risk of thromboembolism. These include presence of a prosthetic valve (particularly mechanical) and atrial fibrillation. The risk of systemic embolization in patients with atrial fibrillation depends on clinical factors, including the presence of HF, hypertension, age, diabetes, and prior thromboembolic events. These issues are discussed in detail separately. (See 'Management approach' above and "Mechanical prosthetic valve thrombosis or obstruction: Clinical manifestations and diagnosis" and "Antithrombotic therapy for mechanical heart valves" and "Atrial fibrillation in adults: Use of oral anticoagulants".)

Risk of intracerebral hemorrhage — Patients with IE are at risk for bleeding complications, particularly intracerebral hemorrhage. In this setting, intracerebral hemorrhage may result from hemorrhagic transformation of an embolic stroke, rupture of a mycotic aneurysm, or septic arteritis with hemorrhage from vessel wall erosions. (See "Complications and outcome of infective endocarditis", section on 'Neurologic complications' and "Overview of infected (mycotic) arterial aneurysm".)

Patients with ischemic stroke are at risk for hemorrhagic transformation with associated worsened prognosis. In a retrospective multicenter cohort of 1345 patients with left-sided IE, 14 percent had ischemic neurologic events and 4 percent had intracerebral hemorrhages [13]. In a review of 4794 patients with IE, approximately two-thirds of the 857 strokes were classified as ischemic, suggesting that up to one-third could be hemorrhagic [14]. The incidence of hemorrhagic transformation in IE in the absence of anticoagulant and/or antiplatelet therapy is unknown; hemorrhagic transformation can range in severity from minimal to catastrophic. The risks of embolization and hemorrhagic transformation for an individual patient depend on a variety of factors including the infectious organism, the size and location of the vegetation, and the coagulation status of the patient. (See "Complications and outcome of infective endocarditis" and "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Risks and prevention of bleeding with oral anticoagulants".)

As discussed below, the effect of antithrombotic therapy on the overall risk of intracerebral hemorrhage in patients with IE is uncertain.

Effect of antithrombotic therapy — The available limited data discussed below do not establish a benefit from anticoagulant or aspirin therapy in reducing the risk of embolism in patients with IE. There is limited evidence on the risk of bleeding complications from antithrombotic therapy in patients with IE.

Antiplatelet therapy — The limited available evidence suggests that antiplatelet therapy does not reduce the risk of embolism in patients with IE.

One observational study suggested that daily antiplatelet therapy for at least six months prior to hospitalization for IE reduced the risk of embolism [15]. However, a later study from the same group found no significant reduction in symptomatic embolic events in those who received prior antiplatelet therapy and instead found fewer events in those receiving continuous statin therapy [16].

The initiation of aspirin after the diagnosis of IE is of no benefit and may be harmful as suggested by a randomized trial in which 115 patients with native or prosthetic IE were assigned to aspirin (325 mg/day) or placebo for four weeks [17]. A prosthetic valve was present in 17 percent of patients in the aspirin group and 26 percent of patients in the placebo group. Anticoagulants were continued in patients with mechanical prosthetic valves. Aspirin did not reduce the incidence of embolic events and had no effect on vegetation resolution or valve function. There was a nonsignificant trend toward a higher incidence of bleeding in patients taking aspirin versus placebo (odds ratio [OR] 1.92, 95% CI 0.76-4.86, p = 0.075).

Anticoagulant therapy — The available evidence is insufficient to establish benefit or safety of anticoagulant therapy in patients with IE. There are no randomized studies of anticoagulant therapy in patients with IE. Observational studies have provided limited information with mixed results as illustrated by the following studies:

●A series dating from 1975 to 1997 of 56 patients with Staphylococcus aureus endocarditis reported a high rate of fatal neurological complications (73 percent) and intracerebral hemorrhage in 21 patients with prosthetic valves (90 percent treated with anticoagulants) [18]. No fatal neurologic events were observed in 35 patients with native valve IE not receiving anticoagulants. A comparison group of patients with prosthetic valves not treated with anticoagulants was not available. Echocardiography was not reported, and most cases of hemorrhagic transformation were diagnosed clinically without confirmation by imaging.

●An association between anticoagulation and reduced cerebrovascular events was found by two overlapping studies based on a database of patients with IE treated from 1996 to 2008 at two academic centers [19,20]:

•In a study of 175 patients with Staphylococcus aureus endocarditis, the 40 patients receiving anticoagulation prior to the onset of IE (73 percent with prosthetic valves) were significantly less likely to experience a major cerebral event (largely ischemic) at the time of admission compared with 135 patients (8 percent with prosthetic valves) not receiving anticoagulation (15 versus 37 percent, adjusted OR 0.27, 95% CI 0.075-0.96) [19]. Brain imaging was performed only in symptomatic patients. At presentation, cerebral hemorrhage was identified in none of the anticoagulated patients and in four patients not receiving anticoagulation. One patient receiving anticoagulation developed a hemorrhagic stroke during hospitalization. In-hospital mortality was similar in patients receiving and not receiving anticoagulation (18 versus 25 percent).

-Among the patients with native valve IE, major cerebral events on admission were more frequent in patients not treated with anticoagulation compared with those who had been treated with anticoagulation (39 versus 0 percent).

-Among patients with prosthetic valve IE, there were similar rates of major cerebral events on admission in not anticoagulated and anticoagulated groups (18 versus 21 percent).

•A study of 570 patients with 587 episodes of native valve IE included 48 in patients receiving warfarin prior to onset of IE [20]. Cerebrovascular complications were significantly less frequent in patients treated with warfarin compared with those treated without warfarin (6 versus 26 percent). No increase in hemorrhagic lesions was detected in patients treated with warfarin compared with patients not treated with warfarin, but this result is uncertain given the limited number of events (2 percent in both groups, 1/48 and 13/539, respectively).

●In a retrospective analysis of a multicenter series of 1345 cases of left-sided IE, independent risk factors for neurologic complications included anticoagulant therapy (hazard ratio [HR] 1.31) as well as vegetation size ≥3 cm, Staphylococcus aureus infection, and mitral valve involvement [13]. Anticoagulant therapy was a risk factor for cerebral hemorrhage (HR 2.71). In adjusted analysis, cerebral hemorrhage and moderate to severe ischemic neurologic events were among the factors independently associated with mortality.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment and prevention of infective endocarditis".)

SUMMARY AND RECOMMENDATIONS

●Patients with infective endocarditis (IE) are at high risk for embolic events, including embolic stroke. Approximately 35 percent of patients with IE have symptomatic cerebrovascular complications and as many as 80 percent of patients have evidence of stroke on imaging. (See 'Evidence' above.)

●Patients with IE are at risk for bleeding complications, particularly intracerebral hemorrhage. In this setting, intracerebral hemorrhage may result from hemorrhagic transformation of an embolic stroke, rupture of a mycotic aneurysm, or septic arteritis with hemorrhage from vessel wall erosions. (See 'Risk of intracerebral hemorrhage' above.)

●The available limited data suggest that neither anticoagulant therapy nor aspirin reduce the risk of embolism in patients with IE. Therefore, anticoagulant or antiplatelet therapy is not indicated to reduce the risk of thromboembolic complications of IE. (See 'Effect of antithrombotic therapy' above.)

●Patients with IE frequently have one or more coexistent conditions that pose a risk of thrombotic complications separate from IE. In such patients, we weigh the risk of withholding antithrombotic therapy against the risk of antithrombotic therapy (particularly the risk of intracerebral hemorrhage). If there is a strong indication for antithrombotic therapy in a patient with IE, we continue antithrombotic therapy after reviewing the echocardiogram and excluding contraindications such as an intracerebral hemorrhage or ischemic stroke by imaging. (See 'Management approach' above.)

•Patients with strong indications for continuing antithrombotic therapy in the setting of IE include those with mechanical prosthetic valves. (See 'Prosthetic valves' above.)

•Antiplatelet therapy for IE patients with coronary artery disease should be governed by the applicable recommendations for coronary artery disease, including specific recommendations for patients who have undergone coronary artery stenting. This includes continuing aspirin indefinitely in all patients with coronary stents, in addition to time-limited dual antiplatelet therapy. The role of antiplatelet therapy in patients with coronary artery disease is discussed separately. (See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy" and "Acute ST-elevation myocardial infarction: Antiplatelet therapy" and "Long-term antiplatelet therapy after coronary artery stenting in stable patients" and "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

•Anticoagulant therapy (rather than antiplatelet therapy) is recommended in IE patients with atrial fibrillation with a CHA₂DS₂-VASc score (table 1) (calculator 1) of 2 or greater. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'.)

•Anticoagulation is recommended in IE patients with atrial fibrillation with mitral stenosis regardless of the CHA₂DS₂-VASc score. (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.)

●In patients with IE in whom a decision is made to continue anticoagulant therapy (eg, for a mechanical valve), we generally replace direct oral anticoagulant (DOAC) or vitamin K antagonist (VKA) therapy (eg, warfarin) with unfractionated heparin or low molecular weight heparin therapy at the time of presentation while stability and the potential need for an invasive procedure is assessed. (See 'Management of antithrombotic therapy if continued' above.)

●Anticoagulant agents should be discontinued in most patients with an acute ischemic stroke and IE. An exception is in patients judged to be at high risk of cardioembolic stroke (above the general risk of stroke associated with IE; eg, a patient with a mechanical valve with high-risk features) who have a small ischemic stroke in whom cautious anticoagulation may be continued, although this recommendation is controversial. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack" and 'Management of antithrombotic therapy if continued' above.)

●In patients who develop an intracerebral hemorrhage or other major bleeding complication, antithrombotic therapy (antiplatelet and anticoagulant therapy) should be immediately discontinued and anticoagulation should be reversed. For those who have been taking warfarin or another VKA, reversal strategies depend upon the severity of the bleeding and the degree of anticoagulation. (See 'Management of antithrombotic therapy if continued' above and 'Intracerebral hemorrhage' above and "Anticoagulation for prosthetic heart valves: Management of bleeding and invasive procedures", section on 'Management of bleeding' and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Treatment of bleeding'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William Gaasch, MD (deceased), who contributed to an earlier version of this topic review.