Background: Incidence of infective endocarditis (IE) is progressively raising because of the increasing number of cardiovascular invasive procedures, support treatment and devices, awareness in the medical community, and improved diagnostic modalities. IE pathophysiology is a unique model of immunothrombosis, and the clinical course is often complicated by either embolic or hemorrhagic events. Managing antithrombotic treatment is challenging and the level of supporting evidence scant. The aim of this review was to discuss and present the embolic and bleeding complication associated with IE and review the available evidence on antithrombotic treatment in patients with IE with and without a previous indication to antithrombotic drugs. Summary: Embolic events occur in 20–40% of patients with IE and are associated with high morbidity and mortality. Acute ischemic stroke is the most common neurological complication. A beneficial effect of antithrombotic therapy in preventing ischemic stroke for patients with IE has never been formally tested in adequately powered randomized clinical trials. Atrial fibrillation is a common complication associated with severe infections, requiring anticoagulation. Furthermore, patients with IE have a high risk of unprovoked and anticoagulation treatment-related bleeding. In particular, intracerebral bleeding is the most severe complication in about 5% of patients with IE. Single antiplatelet therapy with low-dose aspirin after hospitalization for IE has been shown to reduce causes mortality within 90 days without an increase of hemorrhagic strokes. In the absence of bleeding complications, recent guidelines recommend to maintain low-dose aspirin. No data are available on the management of patients with IE while on dual antiplatelet therapy. Key Messages: Several gaps in knowledge remain about antithrombotic management in patients with IE and most of the evidence relies on observational studies. Individualized strategies based on clinical evaluation, comorbidities, patient engagement, and shared decisions strategies are encouraged.

A bidirectional link exists between cardiovascular and infective diseases. Infections increase the risk of thrombotic events, both in the short and long term [1]. At the same time, patients with, or at high risk for, thrombotic disease are more susceptible to infections and infection-related complications [2, 3]. We have recently co-authored an ESC clinical consensus document on the management of antithrombotic therapy in patients with severe infections and an ongoing indication to antithrombotic treatment [4]. In the present review, we discuss indications and management of antithrombotic therapy in patients with infective endocarditis (IE).

Epidemiological Notes

The incidence of IE is increasing worldwide [5]. A recent global survey estimated an age-standardized incidence rate, expressed as cases/100,000 people and 95% uncertainty interval, of 13.8 (11.59–16.34) in 2019 versus 9.91 (8.24–11.84) in 1990. This sharp rise can be explained by several factors: an increasing number of implantations of intracardiac electronic devices, percutaneous intravascular procedures, and support treatments (e.g., dialysis) as well as an increased awareness and improved diagnostic work up. On the other side, rheumatic heart valve disease is becoming a less relevant underlying cause in both high- and low-income countries [6]. Mortality rates are high: the in-hospital mortality of IE is approximately 18–25% and 1-year mortality is up to 40% [7].

Etiology and Pathophysiology of IE

Bacteremia precedes the onset of IE. Usually gram-positive staphylococci, streptococci, and enterococci species that colonize the skin or are part of the oral flora, enter the bloodstream and colonize the endocardium, the endothelial surface of cardiac valves. Native and healthy valves with intact endocardium are naturally resistant to bacterial infection. Nevertheless, IE often occurs on structurally normal heart valves [8, 9]. In the presence of diseased native or prosthetic cardiac valve, the associated low-grade inflammatory response driven by the dysfunctional endothelium and the consequent high shear stress [10], create a favorable docking site for the invading pathogen to colonize the diseased valve. The macroscopic appearance of the bacterial colonization of a cardiac valve is commonly called “vegetation.” Vegetations on the right-sided cardiac valves, the tricuspid and pulmonary valve, are more common in patients addicted to intravenous drug abuse: the repeated intravenous injections of contaminating particulate material causes a chronic endocardial inflammation that represents a substrate for bacterial colonization [10‒12]. On the contrary, vegetations on the left-sided cardiac valves, the mitralis and aortic valves, are more commonly observed in patients with native diseased valves, as a result of both congenital and acquired diseases, or with prosthetic valves. Embolism originates from dislodgment or fragmentation of the cardiac vegetations. Vegetations on the aortic valve associate with an increased risk of systemic embolism, cerebral, coronary, and splenic being the most frequent sites, while vegetations on the pulmonary valve can cause pulmonary embolism.

Immunothrombosis

In response to the bacterial invasion and colonization, a concerted reaction of the immune and hemostatic systems, so-called immunothrombosis, occur [4] and participate to the onset and development of cardiac valve vegetations [10]. Regardless of the underlying etiology, an erosion of the endocardial surface triggers both molecular and hemodynamic responses that facilitate adherence of bacteria (see Fig. 1). Platelets bind bacteria via pattern recognition receptors leading to platelet activation and the secretion of antimicrobial peptides [13]. Therefore, platelets can present bacteria to neutrophils and boost neutrophil activation with neutrophil extracellular trap formation [10]. The innate immune system cells together with killed bacteria components can further promote the activation of the coagulation cascade via the extrinsic and intrinsic pathways. The exposure of tissue factor by monocytes, infected endothelial cell and by the subendothelial matrix, in cases of endocardial damage, activates the extrinsic pathway. Meanwhile, the DNA or RNA from dying and apoptotic cells, bacterial cell wall components, promotes the intrinsic pathway (catalyzing the activation of factor XII (FXII) to FXIIa). The intrinsic and extrinsic pathways converge in the common pathway that ultimately generates thrombin. Thrombin converts soluble fibrinogen into insoluble fibrin, which can act as a scaffold for platelets, white blood cells that fuel local inflammation as well as for bacteria. These mechanisms result in sealing off the infected tissue, protecting bacteria also from antibiotic exposure [10]. Staphylococcus aureus, in particular, exploits this protective mechanism by the production of coagulases, proteins that bind directly to prothrombin determining a non-proteolytic activation. In this way, the bacterium creates a niche which shelters bacteria’s growth to create growing bacterial colonies within fibrin [14]. An intracardiac vegetation consisting of bacteria, leukocytes, fibrin, and platelets, if untreated, can cause systemic/pulmonary septic embolism or valve destruction. Diagnostic criteria as well as principles for antibiotic therapy and indication to surgery have been recently revised and reported in international guidelines [15, 16]. Antibiotics are the mainstay of IE treatment [17]. Choice of the antibiotic is dependent on the pathogen, its sensibility spectrum and on the characteristics of the patient (comorbidities, kidney function, interactions with concomitant drugs). Cardiac surgery is indicated in patients with heart failure due to valve dysfunction, mobile and large vegetations at high risk for systemic embolism, and/or lack of improvement despite appropriate antibiotic treatment.

Fig. 1.

Schematic representation of the pathophysiology of aortic valve endocarditis, the most common clinical complications and the summary of the current recommendations in patients with preexisting indication to antithrombotic therapy. Upper panel: as result of invasive or semi-invasive procedures, some bacteria can access to the bloodstream and join directly to damaged or inflamed cardiac valve endothelium. The innate immune response is the first mechanism for host defense. Indeed, the infected endothelium switches into a prothrombotic state and express cytokines and chemokines involved in the recruitment and activation of platelets and leukocytes in the attempt to contain the infection. Activated platelets bind bacteria and boost neutrophil activation with neutrophil extracellular traps formation (NET). These innate immune cells together with killed bacteria (gray) components also promote the initiation of the coagulation cascade by activation of the extrinsic and intrinsic pathway. The exposure of tissue factor by monocytes, infected endothelial cell and by subendothelial matrix in cases of endothelial damages activates the coagulation extrinsic pathway. The intrinsic and extrinsic pathways converge in the common pathway that begins with the conversion of prothrombin into thrombin. Middle panel: the thrombin converts soluble fibrinogen into insoluble fibrin strands, which, on the one hand, act as a scaffold for platelets and white blood cells that fuel local inflammation and on the other hand prevent further bacterial spread by sealing off the infected tissue. Lower panel: emboli from the infected valve may reach the brain, spleen, myocardium, and the kidney as well as give rise to a mycotic aneurysm in different vascular beds. Treatment with oral anticoagulant drugs should be suspended at least during the first 2 weeks from the IE diagnosis, as the bleeding risk is high and because of possible the need of heart surgery. Antiplatelet therapy should be discussed on an individual basis.

Fig. 1.

Schematic representation of the pathophysiology of aortic valve endocarditis, the most common clinical complications and the summary of the current recommendations in patients with preexisting indication to antithrombotic therapy. Upper panel: as result of invasive or semi-invasive procedures, some bacteria can access to the bloodstream and join directly to damaged or inflamed cardiac valve endothelium. The innate immune response is the first mechanism for host defense. Indeed, the infected endothelium switches into a prothrombotic state and express cytokines and chemokines involved in the recruitment and activation of platelets and leukocytes in the attempt to contain the infection. Activated platelets bind bacteria and boost neutrophil activation with neutrophil extracellular traps formation (NET). These innate immune cells together with killed bacteria (gray) components also promote the initiation of the coagulation cascade by activation of the extrinsic and intrinsic pathway. The exposure of tissue factor by monocytes, infected endothelial cell and by subendothelial matrix in cases of endothelial damages activates the coagulation extrinsic pathway. The intrinsic and extrinsic pathways converge in the common pathway that begins with the conversion of prothrombin into thrombin. Middle panel: the thrombin converts soluble fibrinogen into insoluble fibrin strands, which, on the one hand, act as a scaffold for platelets and white blood cells that fuel local inflammation and on the other hand prevent further bacterial spread by sealing off the infected tissue. Lower panel: emboli from the infected valve may reach the brain, spleen, myocardium, and the kidney as well as give rise to a mycotic aneurysm in different vascular beds. Treatment with oral anticoagulant drugs should be suspended at least during the first 2 weeks from the IE diagnosis, as the bleeding risk is high and because of possible the need of heart surgery. Antiplatelet therapy should be discussed on an individual basis.

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Systemic Embolism

Embolic events occur in 20–40% of IE patients and are associated with increased morbidity and mortality [7]. The risk of systemic embolism is maximal during the first days of IE even after initiation of antibiotic treatment and decreases after 2 weeks [15]. Factors associated with a high thromboembolic risk are related to the vegetation’s size (>10 mm) and mobility [15] and its localization (anterior leaflet of the mitral valve) [18]. Early surgery is associated with a reduction of embolic complications in patients with left-sided IE, severe valvular heart disease, and large vegetations (>10 mm) [18]. Left-side vegetations are associated with systemic embolism in 20–50% of cases. Cerebral embolism is a leading cause of death in IE, and it typically affects the middle cerebral artery in more than 40% of the cases [19]. Although acute ischemic stroke is the most common neurological complication of IE, with a prevalence (%) between 17 [20] and 35 [21] in different studies, cerebral embolism may also manifest as transient ischemic attack or subclinical embolism [22]. Embolization can also involve the meningeal arteries and cause meningitis [23]. Intracranial mycotic aneurysms or intracerebral abscess can also occur [23]. Myocardial infarction caused by septic coronary embolism has a relatively low prevalence (%) ranging from 3 to 11, as compared with other embolic complications [24]. However, ST-elevation myocardial infarction complicating IE has a high in-hospital (41%) and 30-day mortality (43%) rates [24]. Coronary embolism can involve all coronary arteries [25] and is more frequent in patients with aortic valve IE due to the anatomical proximity between the aortic vegetations and the coronary ostia [26]. Beside coronary embolism, other mechanisms of myocardial ischemia during IE could be the occlusion of the coronary ostium by an aortic vegetation, severe aortic regurgitation that decreases coronary perfusion pressure, and rupture/erosion of preexisting atherosclerotic plaques driven from the acute inflammatory response to infection [26]. The most common abdominal embolism site is the spleen with splenic infarction, hemorrhage, rupture, and abscess as most common complications. Splenic abscess is a rare but potentially fatal complication of splenic septic embolism [27]. Right-side endocarditis is associated with septic pulmonary embolism, whose most common symptoms are fever, cough, pleuritic chest pain, and hemoptysis. Right-sided IE prognosis seems to differ based upon the underlying etiology [28].

Thromboprophylaxis

Antiplatelet Therapy

Given the role of platelets in the pathogenesis of IE-associated vegetation, a potential benefit of antiplatelet therapy has been hypothesized for the primary prevention of both IE and IE-associated thromboembolism. Since the network of fibrin and platelets on the damaged endocardium provides a docking site for bacteria, it was hypothesized that platelet inhibition could impair bacterial attachment to the endocardium. In experimental animal models of IE, aspirin treatment reduced the vegetation growth and bacterial titer as well as platelet-bacterial interactions [29]. In staphylococcus aureus’s experimental models of IE, aspirin treatment decreased vegetation weight, echocardiographic vegetation growth, and renal embolic lesions [30]. Efficacy and safety of aspirin treatment were tested in the MATIE (Multicenter Aspirin Trail in Infective Endocarditis) trial. There was no significant reduction of embolic events in patients treated with aspirin started about 34 days after IE onset, while there was a trend toward a higher incidence of bleeding [31]. However, the benefit of aspirin started early at diagnosis is unknown. At present, aspirin or any another antiplatelet agent is not recommended as adjunctive prophylactic therapy in IE by the American Heart Association guidelines (class III; level of evidence: B) [32].

Patients with a Preexisting Indication to Antiplatelet Treatment

A retrospective cohort study of patients with IE who received daily antiplatelet therapy for at least 6 months prior to the hospital admission showed that embolic events and related morbidity occurred significantly less in those on prior antiplatelet therapy [33]. Similarly, an observational study of patients excluded from the MATIE trial because of long-term aspirin use, suggests that aspirin before and at IE onset did not reduce the risk of embolic events with a trend toward increased bleeding [34]. A recent metanalysis has analyzed risk of bleeding, thromboembolism, and death in IE patients with prior anticoagulation or antiplatelet therapy versus those without demonstrates a benefit of antiplatelet therapy, mainly low-dose aspirin, in reducing systemic embolism, without increasing the risk of intracerebral hemorrhage [35]. However, this metanalysis includes studies that consider the effect of patients with a preexisting indication for antiplatelet therapy and it does not provide information about whether the antiplatelet therapy was continued after hospital admission. Only one retrospective observational study analyzed the effect of chronic antiplatelet therapy (defined as use of aspirin or clopidogrel for ≥6 months prior to admission because of coronary heart disease, peripheral vascular disease, cerebrovascular disease, diabetes, or chronic renal failure) and its continuation after admission for IE [36]. In this study, antiplatelet therapy was associated with lower all-cause mortality at 90 days (adjusted OR 0.27, 95% CI: 0.11–0.64) but not with a reduction of cardioembolic events. Moreover, antiplatelet therapy did not increase hemorrhagic strokes also in patients who continued therapy after admission [21]. There are no specific studies that explore the outcome of patients with IE and an indication for DAPT and, again, the management of therapy must be individualized based on the thrombotic/hemorrhagic risk of the individual patient. Table 1 summarizes the studies on antiplatelet therapy on IE. The American Heart Association Guidelines recommend continuation of long-term single antiplatelet therapy at the time of development of IE, in the absence of bleeding complications (class IIb; level of evidence: B) [32].

Table 1.

Summary of main studies on antiplatelet therapy in infective endocarditis

First AuthorDesign of studyPopulation under studyType of antiplatelet therapy under studyMajor endpointsOutcomes
Anavekar et al. [33Retrospective, single-center 600 patients with IE and daily antiplatelet therapy for at least 6 months prior to the admission Aspirin (≤81 mg/day, 81 mg/day, 225 mg/day, 325 mg/day, and ≥325 mg/day), dipyridamole, clopidogrel, ticlopidine, or combination Primary endpoint: symptomatic embolic event that occurred prior to or during hospitalization • Significant reduction in embolic event 12.0% in antiplatelet arm versus 27.8% control; p < 0.001 
 Secondary endpoint: all-cause mortality within the first 6 months of diagnosis of IE • Not collect data about complications involving bleeding 
• No difference in 6-month mortality 
Chan et al. [31Randomized, double-blinded, placebo-controlled, multicenter trial 115 patients with IE 60 assigned to aspirin and 55 assigned to placebo at distance of ∼34 days after the onset of symptoms Aspirin (325 mg/day) Primary endpoint: clinical embolic events involving the brain or other organs • Not significant reduction in embolic event (28.3% on aspirin arm and 20.0% on placebo arm). OR of 1.62; 95% CI: 0.68–3.86; p = 0.29 
Secondary endpoint: subclinical strokes detected by cerebral computed tomography, death, major or minor bleeding, valve surgery, and echocardiographic progression of valvular involvement • Trend toward a higher incidence of bleeding in aspirin versus placebo (OR 1.92, 95% CI: 0.76–4.86; p = 0.075) 
Chan et al. [34Observational, prospective cohort study 560 patients with IE (84 patients excluded from the MATIE because of long-term aspirin use) compared with 55 patients randomized to the placebo arm Aspirin (most common dosage was 325 mg per day) Primary endpoint: clinical embolic events involving the brain or other organs • Long-term aspirin use had no impact on the risk of embolism in either the unadjusted model (OR 0.80; p = 0.582) or the adjusted model (AOR 0.91; p = 0.825) 
• Trend toward excess bleeding in long-term aspirin recipients, compared with placebo recipients (AOR 2.08 95% CI [0.83–5.23]; p = 0.118) 
Pepin et al. [36Observational, retrospective, single-center 241 patients with IE: 75 with chronic antiplatelet therapy prior to developing endocarditis, 166 without prior chronic antiplatelet therapy Low-dose aspirin, clopidogrel 75 mg or combination Primary outcome: all-cause mortality within 90 days of diagnosis • Chronic antiplatelet therapy before IE correlated with a lower mortality (AOR 0.27, 95% CI 0.11–0.64; p <0.05) 
 Secondary outcome: development of major systemic embolism • Chronic antiplatelet therapy was not associated with a significantly lower risk of major embolism 
• Bleeding tended to be more frequent in the aspirin group (p = 0.075) 
Snygg-Martin et al. [21Observational, prospective cohort study 684 patients with left-sided IE (157 with previously stablished antiplatelet therapy (96% acetylsalicylic acid) and 517 as control group Aspirin (77.0% of patients receiving ≤75 mg and only 3.2% receiving doses over 200 mg/day), aspirin and dipyridamole dosage not indicated or clopidogrel 75 mg Primary outcome: incidence of cerebrovascular complications (including ischemic and hemorrhagic strokes and transient ischemic attacks or cerebral infections) at admission or during treatment • No difference in cerebrovascular complications (23.6% vs. 25.0%, AOR 0.8, 95% CI: 0.48–1.5) 
• Intracranial hemorrhages have no correlation to chronic antiplatelet therapy (OR 0,22; CI: 95% 0.03–1.67) 
• Trend toward high in-hospital mortality in previously stablished antiplatelet therapy group (17.8% vs. 12.7%; OR 1.5, 95% CI: 0.9–2.4) 
First AuthorDesign of studyPopulation under studyType of antiplatelet therapy under studyMajor endpointsOutcomes
Anavekar et al. [33Retrospective, single-center 600 patients with IE and daily antiplatelet therapy for at least 6 months prior to the admission Aspirin (≤81 mg/day, 81 mg/day, 225 mg/day, 325 mg/day, and ≥325 mg/day), dipyridamole, clopidogrel, ticlopidine, or combination Primary endpoint: symptomatic embolic event that occurred prior to or during hospitalization • Significant reduction in embolic event 12.0% in antiplatelet arm versus 27.8% control; p < 0.001 
 Secondary endpoint: all-cause mortality within the first 6 months of diagnosis of IE • Not collect data about complications involving bleeding 
• No difference in 6-month mortality 
Chan et al. [31Randomized, double-blinded, placebo-controlled, multicenter trial 115 patients with IE 60 assigned to aspirin and 55 assigned to placebo at distance of ∼34 days after the onset of symptoms Aspirin (325 mg/day) Primary endpoint: clinical embolic events involving the brain or other organs • Not significant reduction in embolic event (28.3% on aspirin arm and 20.0% on placebo arm). OR of 1.62; 95% CI: 0.68–3.86; p = 0.29 
Secondary endpoint: subclinical strokes detected by cerebral computed tomography, death, major or minor bleeding, valve surgery, and echocardiographic progression of valvular involvement • Trend toward a higher incidence of bleeding in aspirin versus placebo (OR 1.92, 95% CI: 0.76–4.86; p = 0.075) 
Chan et al. [34Observational, prospective cohort study 560 patients with IE (84 patients excluded from the MATIE because of long-term aspirin use) compared with 55 patients randomized to the placebo arm Aspirin (most common dosage was 325 mg per day) Primary endpoint: clinical embolic events involving the brain or other organs • Long-term aspirin use had no impact on the risk of embolism in either the unadjusted model (OR 0.80; p = 0.582) or the adjusted model (AOR 0.91; p = 0.825) 
• Trend toward excess bleeding in long-term aspirin recipients, compared with placebo recipients (AOR 2.08 95% CI [0.83–5.23]; p = 0.118) 
Pepin et al. [36Observational, retrospective, single-center 241 patients with IE: 75 with chronic antiplatelet therapy prior to developing endocarditis, 166 without prior chronic antiplatelet therapy Low-dose aspirin, clopidogrel 75 mg or combination Primary outcome: all-cause mortality within 90 days of diagnosis • Chronic antiplatelet therapy before IE correlated with a lower mortality (AOR 0.27, 95% CI 0.11–0.64; p <0.05) 
 Secondary outcome: development of major systemic embolism • Chronic antiplatelet therapy was not associated with a significantly lower risk of major embolism 
• Bleeding tended to be more frequent in the aspirin group (p = 0.075) 
Snygg-Martin et al. [21Observational, prospective cohort study 684 patients with left-sided IE (157 with previously stablished antiplatelet therapy (96% acetylsalicylic acid) and 517 as control group Aspirin (77.0% of patients receiving ≤75 mg and only 3.2% receiving doses over 200 mg/day), aspirin and dipyridamole dosage not indicated or clopidogrel 75 mg Primary outcome: incidence of cerebrovascular complications (including ischemic and hemorrhagic strokes and transient ischemic attacks or cerebral infections) at admission or during treatment • No difference in cerebrovascular complications (23.6% vs. 25.0%, AOR 0.8, 95% CI: 0.48–1.5) 
• Intracranial hemorrhages have no correlation to chronic antiplatelet therapy (OR 0,22; CI: 95% 0.03–1.67) 
• Trend toward high in-hospital mortality in previously stablished antiplatelet therapy group (17.8% vs. 12.7%; OR 1.5, 95% CI: 0.9–2.4) 

OR, odds ratio; AOR, adjusted odds ratio.

Anticoagulant Therapy

A recent observational study investigated the 30- and 90-day mortality, thromboembolism, and bleeding in 7,000 IE patients on VKA started within 14 days from IE diagnosis (n= 743) as compared to IE patients not receiving VKA [37]. After propensity score matching, no difference was observed in the risk of ischemic stroke; however, patients treated with VKA had a reduced risk of all-cause mortality at 30 and 90 days with an hazard ratio of 0.41 (95% CI: 0.28–0.58) and 0.50 (95% CI: 0.39–0.65), respectively. The risk of intracerebral and gastrointestinal bleeding was not significantly different between the two groups; however, a trend toward an increasing risk for intracranial hemorrhage was observed with VKA at 30 and 90 days with a hazard ratio of 1.57 and 95% CI (0.80–3.07) and 1.25 and 95% CI (0.77–2.04), respectively [37].

Patients with a Preexisting Indication to Anticoagulant Therapy

The management of patients with an ongoing antithrombotic treatment at the time of IE represents a clinical challenge given the high risk of both thrombosis and bleeding during severe infections [4]. There is a lack of randomized clinical trial addressing efficacy and safety of anticoagulant therapy type and continuation in patients with IE. The recent ESC guidelines do not provide clear indications on when and whether to continue or suspend anticoagulant/antiplatelet therapy [15]. Patients with mechanical prosthetic valve and IE are at increased risk of thromboembolism and prosthetic valve thrombosis. The risk of thromboembolism is higher in the presence of a mechanical mitral valve as compared to aortic valve and within the first 90 days after valve replacement surgery. Prosthetic valve thrombosis on mitral valves is also associated with high mortality risk [38]. There is scant evidence and few studies addressing management of ongoing anticoagulant therapy during the acute phase of IE. Recently, a metanalysis involving a total of 12,000 patients with IE, of which 9,743 already on VKA for different indications, did not show any difference in in-hospital or 6 weeks mortality rate as well as in the risk of symptomatic ischemic or bleeding cerebrovascular events between VKA treated and non-VKA treated patients [35]. Similarly, a small retrospective cohort study including 258 patients, on oral anticoagulation (n = 50), for different indications versus patients without (n = 208) anticoagulant therapy at time of IE diagnosis, showed no difference in incident stroke, or intracranial hemorrhage within 10 weeks of follow-up [39]. No studies have been performed on patients on treatment with direct oral anticoagulant and IE. Anticoagulation therapy, in staphylococcus aureus IE, was reported to be associated with an increased risk of both ischemic and hemorrhagic cerebrovascular insults [40, 41]. Based on the current knowledge, guidelines recommend discontinuation of oral anticoagulation during the first 2 weeks from IE as this is the time with the highest risk for bleeding (AHA guidelines class of recommendation 2b, level of evidence: B non-randomized) [18] and to switch to LMWH or UFH at appropriate dosing. Of importance, an increased risk of ICH has been reported in IE patients bridged with UFH [18, 32].

Ischemic Stroke

In patients with IE and ischemic stroke or prosthetic valve thrombosis, treatment with thrombolysis is not recommended as the risk of intracerebral bleeding is deemed too high. The efficacy and safety of systemic thrombolysis in acute ischemic stroke is unknown, and it is not recommended by the last ESC guidelines due to the increased risk of intracranial hemorrhage (class III; level of evidence: C) [15]. Mechanical thrombectomy may be considered in selected cases, while in case of large infective aneurysms, neurosurgery, or endovascular therapy is recommended [15]. A French retrospective analysis about the impact of mechanical thrombectomy in patients with IE-related acute stroke demonstrated that this technique presents similar safety and successful reperfusion rate as compared to patients with non-IE cardioembolic stroke [42]. Thrombolytic treatment is not indicated in IE with embolic stroke (class III, level of evidence: B) [15]. Anticoagulation should be discontinued after cerebral embolism for at least 2 weeks as the risk of hemorrhagic transformation is very high in IE patients. UFH should be carefully started with an aPTT of 50–70 s [32]. Cerebral thromboembolism is an indication to early cardiac valve surgery. In the presence of transient ischemic attack or ischemic stroke, cardiac surgery is recommended by the ESC guidelines as early as possible especially in the presence of heart failure, or other septic complications and in absence of coma (class I, level of evidence: B) [15]. A contraindication to early cardiac valve surgery is radiologic evidence of intracerebral bleeding. Patients with hemorrhagic stroke and IE have a prohibitively high surgical risk for at least 4 weeks after the hemorrhagic event. In these patients, serial radiological examinations of the brain are also recommended to exclude microbleedings [43] and cardiac surgery should be delayed at least 4 weeks according to ESC guidelines (class IIa, level of evidence: C) [15].

Myocardial Infarction

There is limited evidence on the efficacy and safety of percutaneous coronary intervention since there is concern about the risk of displacing the infective vegetation and triggering systemic emboli during coronary angiography [44]. Moreover, stent implantation may be associated with the risk of stent infection or generation of coronary artery mycotic aneurysm [26].

Atrial Fibrillation

New-onset atrial fibrillation (AF) represents an independent risk factor for in-hospital mortality in IE patients [45]. Although there are no studies that validate the predictive capacity of the CHA2DS2-VASc score in patient with IE-associated AF, this score is commonly used also in this clinical setting. A small cross-sectional study suggests a role of CHA2DS2-VASc as a tool to predict in-hospital mortality among patient with IE [46]. There are not specific indications on type, dose and time for starting treatment in IE patients with new-onset AF.

Spontaneous Bleeding

Patients with IE have a high risk of spontaneous bleeding. Table 2 summarized the risk factors for intracerebral bleeding [47, 48], the most feared complication that occurs in about 5% of IE patients with IE [49‒51]. The most common underlying causes are primary intracerebral hemorrhage or hemorrhagic transformation of a cardioembolic ischemic stroke. Rupture of a mycotic aneurysm is a common cause of intracerebral bleeding [52]. A retrospective study of 168 patients with IE showed that about 9% of patients who underwent cerebral angiography had a mycotic aneurysms [53]. The sepsis and septic shock can also trigger fibrinolysis activation, which sustain bleeding events [4]. The bleeding diathesis of patients with IE is clinically important since these patients often need open-heart surgery for cardiac valve intervention. Indeed, the incidence of bleeding complications and transfusion requirement after open-heart surgery is higher in patients with IE as compared to those without IE [54].

Table 2.

Predictors of intracerebral bleeding in infective endocarditis

Risk factor for intracerebral bleeding
Staphylococcus aureus endocarditis (1, 2) 
Fungal endocarditis (1) (3) 
Cerebral microbleeds at MRI (4) 
Acute ischemic stroke (1) (3) 
Anticoagulation therapy (1, 2) 
Vegetation size ≥ 30 mm (1) 
Risk factor for intracerebral bleeding
Staphylococcus aureus endocarditis (1, 2) 
Fungal endocarditis (1) (3) 
Cerebral microbleeds at MRI (4) 
Acute ischemic stroke (1) (3) 
Anticoagulation therapy (1, 2) 
Vegetation size ≥ 30 mm (1) 

Infective endocarditis is complicated by either thrombotic or hemorrhagic events so the management of antithrombotic therapy in this condition is challenging. The majority of the evidence relies on observational or retrospective studies and there are many gaps in knowledge to be addressed. Individualized strategies based on clinical evaluation, patient engagement and shared decisions strategies are encouraged.

The authors have no conflicts of interest to declare.

This study was funded in part by Institutional Funding Linea D1 2023 (to B.R.) and supported by a funding from the Swedish Research Council and Swedish Heart and Lung foundation (to B.G.). The funders had no role in the design, data collection, data analysis, and reporting of this study.

C.M: draft and revision; B.R.: revision of the document; B.G.: design, draft, and revision.

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