Echocardiographic defi- nitions of stenosis severity have been provided by the American Society of Echocardiography.1 Obstruction of a mechanical valve may be caused by thrombus for- mation that leads to abnormal leaflet mobility, pannus ingrowth, or a combination of the two.8 Bioprosthetic valve stenosis may be caused by structural valve dete- rioration, with leaflet degeneration by thickening, cal- cification, or tear as the end stage of a slowly progres- sive process resulting in abnormal leaflet motion, or it may be attributable to other structural causes, includ- ing stent creep. Bioprosthetic valve stenosis may also be attributable to nonstructural causes, such as endocardi- tis, leaflet thrombus, or pannus. The progressive stages are defined by the Valve Academic Research Consor- Recommendation-Specific Supportive Text 1. TTE and TEE assessment can appropriately detect and quantify prosthetic valve stenosis.1 TTE within 3 months after valve implantation is useful to provide baseline data on valve hemodynamics and ventricular function. In some patients, the orifice area of the implanted prosthesis may be inadequate to meet the cardiac output demands of the patient, even when the prosthetic valve itself is functioning normally. This circumstance, termed patient prosthesis mismatch, is associ- ated with a high transvalvular gradient, per- sistent LV hypertrophy, and an increased rate of cardiac events after valve replacement.10,11 Diagnosis in the setting of bileaflet mechanical valves is complicated by nonlaminar patterns of blood flow, for which significant pressure recovery may be present; thus, a high velocity in the central narrow slit-like orifice may not cor- relate with prosthetic valve stenosis or patient prosthesis mismatch. Prosthetic valve stenosis is distinguished from patient prosthesis mismatch by comparison with the early postoperative base- line study and by visualization of the appearance and motion of the valve leaflets. Prosthetic valve stenosis is characterized by a clinical course of progressive increase in transvalvular velocity and pressure gradient in conjunction with abnormal thickened/calcified leaflets (for bioprosthetic valves) or evidence of pannus formation (with mechanical valves). 2. The motion of the leaflets of a mechanical valve is best evaluated radiographically with fluoros- copy or cine-CT imaging because strong reflec- tions from the mechanical valve obscure motion on echocardiographic imaging in most patients, particularly as assessed on images from the trans- thoracic approach. With fluoroscopic imaging, the angle of imaging must be adjusted to dem- onstrate leaflet motion from a side view, permit- ting measurement of the angles of opening and closure that can be compared with expected values for that valve type. Cine-CT images are obtained at a high frame rate focused on the prosthetic valve in a 3D acquisition. Compared with fluoroscopy, cine-CT 3D images are less operator dependent for measuring opening and closing angles. In addition, cine-CT allows detection of pannus or thrombus on or adjacent Table 23. Systemic Fibrinolysis Versus Surgery for Prosthetic Valve Thrombosis Favor Surgery Favor Fibrinolysis Readily available surgical expertise No surgical expertise available Low surgical risk High surgical risk Contraindication to fibrinolysis No contraindication to fibrinolysis Recurrent valve thrombosis First-time episode of valve thrombosis NYHA class IV NYHA class I, II, or III ) Small clot ( 0.8 cm2 ) LA thrombus No LA thrombus Concomitant CAD in need of revascularization No or mild CAD Other valve disease No other valve disease Possible pannus Thrombus visualized Patient choice Patient choice CAD indicates coronary artery disease; and NYHA, New York Heart Association. Adapted from several references.2,5,7,13,14 CLINICAL STATEMENTS AND GUIDELINES to the valve, which is not possible with fluoros- copy. When excessive gradients are present with normal leaflet motion and no thrombus, either patient prosthesis mismatch or pannus forma- tion is present (or both). 3. Stenosis of a bioprosthesis may occur because of progressive structural valve degeneration or pan- nus formation. However, stenosis can also occur because of a thin layer of thrombus on the valve cusps, which is reversible with oral anticoagula- tion therapy. Bioprosthetic valves are less throm- bogenic than their mechanical counterparts. However, the diagnosis of subclinical bioprosthetic valve thrombosis has increased with the use of CT imaging and as a function of the increased num- bers of implanted bioprosthetic valves, including When there is clinical evidence of biopros- thetic valve stenosis, 3D TEE or 4D CT imaging may be useful to detect a layer of valve thrombus as the cause of the obstruction. 11.8.2. Intervention for Prosthetic Valve Stenosis Recommendations for Intervention for Prosthetic Valve Stenosis Referenced studies that support the recommendations are summarized in Online Data Supplement 40. COR LOE Recommendations In patients with symptomatic severe stenosis of a bioprosthetic or mechanical prosthetic valve, repeat surgical intervention is indicated unless surgical risk is high or prohibitive.1 3 For severely symptomatic patients with bioprosthetic aortic valve stenosis and high or prohibitive surgical risk, a transcatheter ViV procedure is reasonable when performed at a Comprehensive Valve Center.4,5 For patients with significant bioprosthetic valve stenosis attributable to suspected or documented valve thrombosis, oral anticoagulation with a VKA is reasonable.6 13 Synopsis Cumulative survival rates are higher with reoperative AVR than with transcatheter ViV treatment for prosthetic valve stenosis, and a surgical approach is associated with a re- duced incidence of patient prosthesis mismatch, reduced incidence of paravalvular leak, and lower aortic valve gra- The VIVID (Valve-In-Valve International Data) reg- istry examined outcomes with ViV treatment of 459 pa- tients, of whom 40% had isolated stenosis and 30% had Within 1 month after the ViV procedure, 7.6% of patients died and 1.7% had a major stroke. Of the survivors, 93% experienced good functional status (NYHA class I or II), with an overall 1-year survival rate of Some systematic reviews comparing outcomes of transcatheter ViV with those of repeat SAVR suggest that hemodynamic outcomes are similar, but stroke and bleeding risks are lower with ViV.15 There is a subset of patients with bioprosthetic valve stenosis attributable to thrombus on the leaflets who may respond to oral anti- coagulation with a VKA (Figure 14).6 13 Recommendation-Specific Supportive Text 1. Reoperative surgery for prosthetic valve stenosis is associated with acceptable mortality and morbid- ity rates in the current era, but the risks are typi- cally higher than those estimated at the time of initial surgery because of older patient age, clini- cal status at the time of intervention, and reop- The decision to proceed with surgical versus transcatheter intervention is based on available expertise, individual patient and valve characteristics, and shared decision-making. 2. Catheter-based therapy with transcatheter ViV has emerged as an acceptable alternative to reopera- tive surgery for the treatment of high and prohib- itive surgical risk patients with bioprosthetic AS.4,5 Although coronary artery obstruction is more com- mon with aortic ViV procedures than with TAVI for native AS, rates of paravalvular leak and permanent pacemaker implantation are lower with aortic ViV procedures than with TAVI for native AS. Annulus rupture has not been reported. Transcatheter ViV also has been successfully performed for failed surgi- cal bioprostheses in the mitral, pulmonic, and tricus- pid positions, although LV outflow obstruction may occur after mitral ViV implantation. 3. A subset of patients presents with stenosis of a bioprosthetic valve attributable to leaflet throm- bosis that results in decreased mobility of the leaf- lets. Leaflet thrombosis can occur from 1 month to years after implantation. If the patient is stable and has no contraindication to long-term anti- coagulation, a trial of oral anticoagulation with VKA may result in resolution of the thrombus and improvement in hemodynamics.6 13 However, these patients are at increased risk of recurrent thrombosis (if the anticoagulation is stopped) and early structural deterioration, and thus they require close follow-up.17 11.9. Prosthetic Valve Regurgitation Regurgitation in a mechanical prosthetic valve may be transvalvular, caused by impaired motion of the valve disk secondary to pannus, thrombus, or vegetation in- terfering with complete closure of the valve occluders, or paravalvular, caused by suture line disruption related to technical error at implantation, suture failure, annu- lar disruption, or endocarditis. Patients with severe mi- tral annular calcification are particularly vulnerable to developing late paravalvular leak. Regurgitation in bio- prosthetic valves may be paravalvular but more often is CLINICAL STATEMENTS AND GUIDELINES transvalvular, caused by leaflet immobility secondary to calcification or leaflet perforation or flail associated with areas of focal calcification.1 Echocardiographic defini- tions of prosthetic valve regurgitation severity have been published by the American Society of Echocardiography.2 11.9.1. Diagnosis of Prosthetic Valve Regurgitation Recommendations for Diagnosis of Prosthetic Valve Regurgitation Referenced studies that support the recommendations are summarized in Online Data Supplement 41. COR LOE Recommendations In patients with suspected mechanical or bioprosthetic valve regurgitation, TTE and TEE are recommended to determine the cause and severity of the leak, assess ventricular function, and estimate pulmonary artery systolic pressure.1 4 In patients undergoing a transcatheter procedure for paravalvular prosthetic regurgitation, 3D TEE is recommended for Synopsis The clinical presentation of prosthetic valve regur- gitation varies depending on its severity, hemody- namic effects, and etiology. In asymptomatic pa- tients, prosthetic valve regurgitation may be found incidentally on routine clinical or imaging follow-up. A change in auscultatory findings (eg, change in prosthetic valve sounds or a new murmur) should prompt suspicion of prosthetic valve dysfunction. Symptomatic patients with prosthetic valve regurgi- tation present with unexplained or new-onset HF or significant hemolysis with or without anemia. TTE is inadequate for evaluation of prosthetic mitral valves; TEE is needed when prosthetic MR is a concern. A critical step in evaluation of the patient with pros- thetic valve regurgitation is to distinguish transval- vular from paravalvular leak, which also requires TEE in addition to TTE. Figure 14. Management of prosthetic valve stenosis and regurgitation. Colors correspond to Table 2. 3D indicates 3-dimensional; 4D, 4-dimensional; CT, computed tomography; CVC, Comprehensive Valve Center; HF, heart failure; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography/echocardiogram; and ViV, valve-in-valve. *See Figure 13 if valve thrombosis is suspected. CLINICAL STATEMENTS AND GUIDELINES Recommendation-Specific Supportive Text 1. Echocardiography is the primary imaging modality to assess the location and quantify the severity of pros- thetic valve regurgitation, often requiring both TTE and TEE approaches.1,3 Although TTE provides supe- rior assessment of transvalvular gradients, chamber sizes, and function, TEE is better suited to identify the cause and location of regurgitation and is essential for prosthetic mitral valve because of acoustic shadow- ing on TTE. Even with prosthetic aortic valves, acous- tic shadowing may affect detection of a paravalvular leak by either TTE or TEE, with TTE being suboptimal to assess posterior paravalvular leak and TEE subop- timal to assess anterior defects.3 The Valve Academic Research Consortium (VARC) has suggested an approach for assessment of paravalvular leak severity and constructed a 5-class grading scheme.7 2. 3D echocardiography plays a significant role in determining the precise location and size of the paravalvular leak in patients undergoing interven- tion. For a successful transcatheter paravalvular leak closure, adequate paravalvular leak assess- ment includes 1) precise location of the defect(s), 2) precise dimensions, 3) orientation of the defect in relation to the sewing ring and prosthetic valve occluders or leaflets, and 4) location and orienta- tion of the subvalvular structures. Real-time 3D TEE allows optimal visualization of the defects and direct guidance for catheter movement and positioning of the implanted device(s) during the transcatheter 3D TEE also allows assessment of residual regurgitation after device placement. Limitations of 3D TEE include artifacts of ultrasound imaging (eg, dropout, acoustic shadowing, rever- beration artifacts) and reduced temporal and spatial Transcatheter closure using intracardiac echocardiography guidance is possible and allevi- ates the need for conscious sedation or anesthesia but allows only 2D and color Doppler imaging.9 11.9.2. Medical Therapy Medical therapy for prosthetic valve regurgitation is ap- propriate in asymptomatic patients or when the cause of regurgitation is valve thrombosis (see Sections 11.6 and 11.8) or prosthetic valve endocarditis (see Section 12.3), although further intervention may ultimately be needed in many of these patients. Some patients tolerate asymp- tomatic prosthetic valve regurgitation for many years, sim- ilar to patients with native valve regurgitation. However, there may be patients who develop rapid progression of the severity of bioprosthetic valve regurgitation because of leaflet degeneration. In patients with hemolytic ane- mia attributable to paravalvular regurgitation, medical management with folic acid and iron supplementation or periodic transfusion may be possible when the anemia is not severe, with intervention reserved for patients with symptomatic intractable anemia (see Section 11.8.3). Recommendations for Intervention Referenced studies that support the recommendations are summarized in Online Data Supplement 41. COR LOE Recommendations In patients with intractable hemolysis or HF attributable to prosthetic transvalvular or paravalvular leak, surgery is recommended unless surgical risk is high or prohibitive.1 4 In asymptomatic patients with severe prosthetic regurgitation and low operative risk, surgery is reasonable.1 4 In patients with prosthetic paravalvular regurgitation with the following: 1) either intractable hemolysis or NYHA class III or IV symptoms and 2) who are at high or prohibitive surgical risk and 3) have anatomic features suitable for catheter-based therapy, percutaneous repair of paravalvular leak is reasonable when performed at a Comprehensive Valve Center.5 9 For patients with severe HF symptoms caused by bioprosthetic valve regurgitation who are at high to prohibitive surgical risk, a transcatheter ViV procedure is reasonable when performed at a Comprehensive Valve Center.10 12 Synopsis Prosthetic valve degeneration can result in regurgitation attributable to leaflet calcification and noncoaptation or leaflet degeneration with a tear or perforation. Acute or chronic severe regurgitation may result in HF symp- toms and signs. Paravalvular leak may result in hemoly- sis with symptoms attributable to anemia and HF. New paravalvular leak late after valve implantation raises the concern for IE, which should be excluded because the presence of infection would require antibiotic treat- ment before surgical therapy and would be a contrain- dication to transcatheter therapy. Symptomatic patients with paravalvular leak around a prosthetic valve are best managed by surgery, with percutaneous closure of the leak if the patient is at high or prohibitive surgical risk. Symptomatic patients with bioprosthetic valve regurgi- tation are best managed by surgery, with a transcath- eter ViV procedure if the patient is at high or prohibitive risk. Because of rapid progression of bioprosthetic re- gurgitation, replacement of a leaking bioprosthesis may be considered even in the asymptomatic patient. Recommendation-Specific Supportive Text 1. Surgery is a viable therapeutic option in many patients with symptomatic paravalvular leak and is associated with reasonable outcomes.1 The risks associated with surgical intervention depend on the procedure required, be it suture repair or CLINICAL STATEMENTS AND GUIDELINES repeat AVR. Although surgical reoperation is asso- ciated with acceptable mortality and morbidity rates in the current era, it still carries a higher risk than the initial surgery. Kaneko and colleagues examined a cohort of 3380 patients from the STS database (2011 2013) who underwent elective isolated reoperative AVR, and they demonstrated a higher (but acceptable) operative mortality rate than that seen with initial AVR (4.6% versus 2.2%; P<0.0001) and relatively low complication This was true even among octogenarians who underwent reoperative AVR.3 In a cohort of 136 consecutive patients who underwent surgical correction for a non endocarditis-related aortic or mitral paravalvular leak (1986 2001), surgical correction of the paravalvular leak was associ- ated with acceptable operative mortality (6.6%) and morbidity rates.1 More recently, Shah and colleagues reported an operative mortality rate of 3% among 495 patients undergoing surgery for paravalvular leak,14 with higher risk associated with mitral than with aortic valve procedures (odds are consistent with the findings of Bouhout and who reported operative mortality rates of 8% among mitral valve, 3% among aor- tic valve, and 14% among double-valve patients in a total cohort of 190 patients undergoing sur- gery indicated for paravalvular leak. Estimates of operative risk for individual patients can be calcu- lated by using the STS risk calculator (http://risk- 2. Prosthetic valve deterioration can result in regurgi- tation attributable to leaflet calcification and non- coaptation or leaflet degeneration with a tear or perforation. Even in asymptomatic patients with severe prosthetic regurgitation, valve replacement is reasonable because of the risk of sudden clini- cal deterioration if further leaflet tearing occurs. IE should be excluded or concurrently treated. If a watchful waiting approach is taken in asymp- tomatic patients with severe prosthetic valve regurgitation, referral to a Comprehensive Heart Valve Center is prudent. 3. In some patients, operative risk is high, or surgery is not feasible. Nonrandomized studies have dem- onstrated clinical success with percutaneous para- valvular leak closure performed by expert operators underthesupervisionofanMDTataComprehensive Valve Center. Procedural success rates for percuta- neous paravalvular leak closure, typically defined by no more than mild residual regurgitation and the absence of death and major complications, are highly variable. In a large single-center cohort, per- cutaneous repair of 141 paravalvular defects was attempted in 115 patients, with an achieved overall success rate of 77% and a 30-day complication rate In another study of 126 patients who underwent percutaneous paravalvular leak repair, Sorajja and colleagues reported a 3-year survival rate of 64.3%.5 The degree of residual regurgita- tion affects symptom improvement and survival. In a cohort of 231 consecutive patients (2006 2017) who underwent percutaneous mitral paravalvu- lar leak closure, the reduction of paravalvular leak to mild or less was achieved in 70% of patients.7,8 Those patients with mild or less residual paravalvular leak had a survival rate at 3 years of 61%, compared with a rate of 47% in patients with greater degrees of residual paravalvular leak (P=0.002).7,8 Notably, treatment of HF symptoms with paravalvular leak closure is more successful than is treatment of hemolysis. IE should be excluded before attempted paravalvular leak repair. 4. The Valve-In-Valve International Data registry examined outcomes of transcatheter ViV proce- lated regurgitation and 30% had mixed lesions.10 Within 1 month after the ViV procedure, 7.6% of patients died, 1.7% had a major stroke, and 93% of survivors experienced good functional sta- tus. The 1-year survival rate was 83.2%.10 Several systematic reviews have compared outcomes of transcatheter ViV with those of reoperative SAVR. In 1 report, ViV had similar hemodynamic out- comes to repeat surgery and lower stroke risk and bleeding risk than repeat surgery.11 A meta-anal- ysis of 498 patients demonstrated no significant differences in early and mid-term all-cause mor- tality rates with ViV or reoperation.17 In another meta-analysis of342 patients, reoperative AVR was compared with transcatheter ViV for failed degenerated aortic bioprosthesis and the group undergoing reoperative AVR had a lower all cause mortality with superior hemodynamic outcomes.18 Thus, although transcatheter ViV appears to be a safe and feasible alternative to repeat SAVR in patients who are inoperable or at high surgical risk, repeat SAVR should remain the standard of care, particularly in low-risk patients.18 12. INFECTIVE ENDOCARDITIS 12.1. Classification of Endocarditis Endocarditis is classified according to whether a native or prosthetic valve is affected and by timing of infec- tion after valve intervention. Prevention of endocardi- tis is important in all patients with valve disease, both before and after valve replacement or intervention (see Section 2.4.2). The risk factors involved with IE and the predominating causative organisms have evolved over CLINICAL STATEMENTS AND GUIDELINES Recommendations for Diagnosis of IE (Continued) COR LOE Recommendations time, with a recent increased incidence of drug use as- sociated IE. IE is fatal unless treated appropriately, and there are no asymptomatic patients with endocarditis. The in-hospital mortality rate for IE is 15% to 20%, with a 1-year mortality rate approaching 40%. Nonin- fective types of endocarditis are not addressed in these guidelines. 12.2. Diagnosis of IE Recommendations for Diagnosis of IE Referenced studies that support the recommendations are summarized in Online Data Supplement 42. COR LOE Recommendations In patients at risk of IE (eg, those with congenital or acquired VHD, previous IE, prosthetic heart valves, certain congenital or heritable heart malformations, immunodeficiency states, or injection drug use) who have unexplained fever blood, culture samples should be obtained.1 In patients with the recent onset of left-sided valve regurgitation, at least 2 sets of blood culture samples should be obtained.1 12 In patients with suspected IE, the Modified Duke Criteria should be used for diagnosis Patients with IE should be evaluated and managed with consultation with a multispecialty Heart Valve Team, which includes an infectious disease specialist, cardiologist, and cardiac surgeon; a cardiac anesthesiologist for surgically managed ; and a neurologist for patients with In patients with suspected IE, TTE is recommended to identify vegetations, characterize the hemodynamic severity of valvular lesions, assess ventricular function and pulmonary pressures, and detect In all patients with known or suspected IE and nondiagnostic TTE results, when complications have developed or are clinically suspected or when intracardiac device leads are present, TEE is recommended.21,23 40 In patients with IE who have a change in clinical signs or symptoms (eg, new murmur, embolism, persistent fever, HF, abscess, or atrioventricular heart block) and in patients at high risk of complications (eg, extensive infected tissue, large vegetation on initial echocardiogram, or staphylococcal, enterococcal, or fungal infections), TTE and/or TEE are recommended for In patients undergoing valve surgery for IE, intraoperative TEE is recommended.47 50 In patients being considered for an early change to oral antibiotic therapy for the treatment of stable IE, a baseline TEE before switching to oral therapy and a repeat TEE 1 to 3 days before completion of the oral antibiotic regimen should be performed.51 In patients with Staphylococcus aureus bacteremia without a known source, TEE is reasonable to diagnose possible IE.11,36,52 56 In patients with a prosthetic valve in the presence of persistent fever without bacteremia or a new murmur, a TEE is reasonable to aid in the diagnosis of IE.57 60 In patients in whom the anatomy cannot be clearly delineated by echocardiography in the setting of suspected paravalvular infections, CT imaging is reasonable.37,61 68 In patients classified by Modified Duke Criteria as having possible IE, F-fluorodeoxyglucose PET/CT is reasonable as adjunct diagnostic imaging.69 71 In patients with nosocomial S. aureus bacteremia with a known portal of entry from an extracardiac source, TEE might be considered to detect concomitant Synopsis In patients with suspected endocarditis, the Modified Duke Criteria (Tables 24 and 25) are the current stan- dard for diagnosis and incorporate clinical, imaging, and bacteriological criteria. These criteria have been well validated by comparison with surgical or autopsy findings and in the clinical outcomes of numerous studies involving a wide spectrum of patients, includ- ing children, the elderly, prosthetic valve recipients, injection drug users, and non drug users, as well as patients in both primary- and tertiary-care settings. For patients with VHD and known or suspected IE, ob- tain blood culture results before initiation of antibiotic therapy. For diagnosis and management of patients with IE, additional members of the Heart Valve MDT include infectious disease experts, who can provide advanced approaches to microbiological diagnosis. Cardiac imaging with TTE, TEE, and now CT and CT/ PET imaging is critical for diagnosis of IE.4,6 10 Recommendation-Specific Supportive Text with IE provided that 2 blood culture samples are obtained at different times, ideally >6 hours apart if clinical status allows, at peripheral sites before initiation of antimicrobial therapy. More important than the time interval of the collection of culture samples is observing strict aseptic tech- nique, avoiding sampling from intravascular lines, and ensuring an adequate volume of blood for the culture sample. Routine incubation of blood culture samples for >7 days is no longer necessary in the era of continuous-monitoring blood culture CLINICAL STATEMENTS AND GUIDELINES systems and non culture-based technology. In the 10% of patients with culture-negative endocar- ditis, serological testing or advanced laboratory diagnostics (eg, polymerase chain reaction) may be helpful to identify the etiologic agent.1,42,75 78 2. The recent onset of new or increased left-sided valve regurgitation, detected by the presence of a new or louder murmur followed by TTE confir- mation, may be attributable to endocarditis, so it is prudent to obtain blood culture samples to exclude this diagnosis. 3. The Modified Duke Criteria (Tables 24 and 25) have been well validated by comparison with surgical or autopsy findings and in the clinical outcomes of numerous studies involving a wide spectrum of patients, including children, the elderly, prosthetic valve recipients, injection drug users, and non drug users, as well as patients in both primary- and tertiary-care settings. About three-fourths of patients with IE are diagnosed within 30 days of the onset of infection, so clas- sic clinical features of IE, such as embolic or vasculitic skin lesions, renal disease caused by immune complex deposition, and immunologic abnormalities, are often absent. In these cases, maintaining a high level of clinical suspicion with regard to the possibility of IE in patients who are susceptible is paramount.4,6 10 4. The diagnosis of IE can still be difficult and is fre- quently delayed, which may cause progressive and potentially irreparable structural damage to the heart and other organ systems second- ary to vascular embolic and immunologically mediated events. Additionally, stroke (16.9%), embolization other than stroke (22.6%), HF (32.3%), intracardiac abscess (14.4%), and the need for surgical therapy (48.2%) remain common. Patients with suspected IE are most optimally managed in an environment that coordinates the management of specialists who are well attuned to the various organ systems, pathological processes, and potential treatment Table 24. Diagnosis of IE According to the Proposed Modified Duke Criteria Definite IE Pathological criteria Microorganisms demonstrated by culture or histological examination of a vegetation, a vegetation that has embolized, or an intracardiac abscess specimen; or Pathological lesions: Vegetation or intracardiac abscess confirmed by histological examination showing active endocarditis Clinical criteria 2 major criteria; or 1 major criterion and 3 minor criteria; or 5 minor criteria Possible IE 1 major criterion and 1 minor criterion; or 3 minor criteria Rejected Firm alternative diagnosis explaining evidence of IE; or Resolution of IE syndrome with antibiotic therapy for <4 d; or No pathological evidence of IE at surgery or autopsy, with antibiotic therapy for <4 d; or Does not meet criteria for possible IE as listed above IE indicates infective endocarditis. Adapted from Durack DT, et al,2 and Li JS, et al.4 Table 25. Major and Minor Criteria in the Modified Duke Criteria for the Diagnosis of IE Major criteria Blood culture positive for IE Typical microorganisms consistent with IE from 2 separate blood cultures: Viridans streptococci, Streptococcus bovis, HACEK group (Haemophilus spp, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella spp, and Kingella kingae), S. aureus; or community-acquired enterococci, in the absence of a primary focus; or Microorganisms consistent with IE from persistently positive blood culture results, defined as follows: At least 2 positive culture results of blood samples drawn 12 h apart; or All of 3 or most of 4 separate culture samples of blood (with first and last samples drawn at least 1 h apart) Single positive blood culture result for Coxiella burnetii or antiphase I IgG antibody titer >1:800 Evidence of endocardial involvement Echocardiogram positive for IE defined as follows: Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation Abscess; or New partial dehiscence of prosthetic valve New valvular regurgitation (worsening or changing of preexisting murmur not sufficient) Minor criteria Predisposition, predisposing heart condition, or injection drug use Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway lesions Immunological phenomena: glomerulonephritis, Osler s nodes, Roth s spots, and rheumatoid factor Microbiological evidence: positive blood culture but does not meet a major criterion as noted above* or serological evidence of active infection with organism consistent with IE *Excludes single positive cultures for coagulase-negative staphylococci and organisms that do not cause IE. IE indicates infective endocarditis; IgG, immunoglobulin G; and spp, species. Adapted from Durack DT, et al,2 and Kupferwasser LI, et al.3 CLINICAL STATEMENTS AND GUIDELINES modalities involved, ideally at centers with immediate access to cardiac surgery during the initial observation stages of the disease. With the emerging use of telemedicine, it may be rea- sonable to manage patients with lower-acuity IE in a center without on-site multispecialty care by telecommunication with a Heart Valve MDT and infectious disease specialists, with rapid transfer of the patient to a Comprehensive Valve Center 5. The presence of valvular vegetation is a major criterion in the diagnosis of IE. TTE has a sen- sitivity between 50% and 90% and a specific- ity >90% for detection of vegetations in native valve endocarditis. TTE has a sensitivity of only 36% to 69% in prosthetic valve endocarditis, but TTE still has a role in these patients for detection and quantitation of valve dysfunction (even in the challenging situation of regurgitation in the mechanical prosthetic mitral valve, for which a proximal convergence zone may provide impor- tant evidence for a paravalvular leak), evalua- tion of ventricular size and systolic function, and estimation of pulmonary pressures. TTE exhibits superior imaging over TEE for the anterior aspect of a prosthetic aortic valve, which is commonly shadowed by the valve on TEE. TTE also allows measurement of aortic transvalvular velocity/ gradient, which is not always possible on TEE. Although TTE will not definitively exclude veg- etations or abscesses in IE, it can identify very high-risk patients, establish the diagnosis, and guide early treatment decisions (Figure 8).14,19 23 6. The sensitivity of TEE in native valve endocarditis ranges from 90% to 100%, with sensitivity ranges slightly lower in prosthetic valve endocarditis. TEE is superior to TTE in the visualization of both veg- etations and paravalvular complications, which can be anatomic (eg, valve perforation, abscesses, and pericardial effusion) or hemodynamic (eg, valve regurgitation, fistulae, and intracardiac thrombi) in nature. TTE and TEE are complementary for the comprehensive evaluation of hemodynamics and anatomy in patients with IE. TEE should be used as an adjunct in patients with echocardiographic fea- tures of IE on TTE to rule out the presence of findings such as abscesses, which may alter the therapeutic approach to the management of the patient. TEE also serves a vital role in reassessment of patients with known IE with suspected clinical complica- tions, as well as a guiding tool in the intraoperative assessment and management of the patient with IE. The timing of repeat examinations depends on the clinical presentation and course and on the vir- ulence of the microorganism. Increasing vegetation size under therapy must be considered a risk fac- tor for new embolic events, whereas unchanged or reduced vegetation size under therapy may be more difficult to interpret.23,29,32 40 7. HF, paravalvular extension, and embolic events represent the 3 most frequent and severe com- plications of IE. They are also the 3 main indi- cations for early surgery, which is performed in almost 50% of cases. If signs or symptoms consistent with any of these complications exist, there should be a very low threshold for repeat imaging in these patients. TEE may miss initial paravalvular abscesses, particularly when the study is performed early in the patient s ill- ness. In such cases, the incipient abscess may be seen only as nonspecific paravalvular thicken- ing, which on repeat imaging across several days may become recognizable as it expands and cav- itates. Similarly, paravalvular fistulae and pseu- doaneurysms develop over time, and negative early TEE images do not exclude the potential for their development. A single negative TEE study cannot rule out underlying IE, and a repeat TEE study should be performed when a suspicion of persistence of infection remains or if complica- tions ensue. Conversely, in the absence of clini- cal deterioration or new signs and symptoms, routine follow-up echocardiography is probably of only limited clinical utility.24,41,42,44 46 8. Intraoperative TEE during cardiac surgery has an important role in the evaluation and quality con- trol of a large variety of pathologies. Clinical and echocardiographic characteristics may change during an episode of IE because of the pro- longed active phase and fluctuating course of this disease. Even if preoperative TEE has been performed, vegetation change/embolization or extension of the infectious process beyond the valve tissue may occur. In addition, other valves may become involved as the disease timeline progresses. Intraoperative TEE has been invalu- able for baseline reassessment of anatomic or hemodynamic changes that may occur in the interval between the diagnostic echocardiogram and the time of surgery. TEE is also an important monitoring tool for evaluation of operative com- plications, such as air emboli, and an important adjunct to ensure the quality of the intended 9. The recently published randomized POET (Partial Oral Treatment of Endocarditis) trial studied 400 patients with stable left-sided IE caused by streptococcus, Enterococcus faecalis, S. aureus, or coagulase-negative staphylococci. Patients who had been on intravenous antibiotics for at CLINICAL STATEMENTS AND GUIDELINES least 10 days were randomized to continuation of the usual course of intravenous antibiotics or discharge to ambulatory treatment with oral antibiotics. As part of the study protocol, patients were reassessed by TEE within 1 to 3 days of completion of their assigned treatment to con- firm that the patient had a sufficient response to therapy. The primary outcome was a composite of all-cause mortality, unplanned cardiac surgery, embolic events, or relapse of bacteremia with the primary pathogen. At 6 months after antibiotic treatment completion, the switch to early oral antibiotic therapy was noninferior to traditional long-term intravenous therapy.51 10. IE in patients with S. aureus bacteremia fre- quently involves normal cardiac valves and is seldom accompanied by the physical stigmata of IE, rendering the diagnosis of the disease dif- ficult. Reliance on physical examination findings and clinical stigmata is likely to result in under- diagnosis of S. aureus IE in a large number of cases. TEE is cost-effective to guide duration of therapy in patients with intravascular catheter associated S. aureus bacteremia, patients with intracardiac electronic devices, or other patients at higher risk of IE (including those with previous prosthetic valve surgery) or associated complica- tions. Despite early diagnosis and appropriate therapy, IE after S. aureus bacteremia is fre- quently associated with disabling and life-threat- ening sequelae. The overall mortality rate of S. aureus IE ranges from 19% to 65%. Other com- plications include HF (20% 50%), paravalvular cardiac abscesses (30% 40%), neurological manifestations (30%), and systemic emboliza- 11. When compared with native valve endocarditis, prosthetic valve endocarditis is characterized by a lower incidence of vegetations (especially in mechanical prostheses) and a higher incidence of annular abscess and other paravalvular complica- tions. Because cardiac auscultation may also be less revealing in prosthetic valve endocarditis and because ordinarily less virulent organisms may cause more anatomic destruction before culture or serological detection, early use of TEE in these high-risk patients is important. The sensitivity of TEE for detecting IE is lower with prosthetic valves than with native valves, so the importance of comparing serial echocardiographic studies is paramount to making the diagnosis.59,60 12. Electrocardiographic-synchronized, multidetector- row CT is emerging as an important tool for non- invasive cardiac assessment and may be helpful in evaluating complications of IE. CT may also be indicated in right-sided IE to demonstrate the pres- ence of septic pulmonary infarcts and abscesses. Although CT is less accurate than TTE and TEE for identifying valvular vegetation and valvular perfo- rations, CT is useful for evaluating patients with equivocal findings on TEE and for evaluating com- plications in patients with suspected paravalvular infection. CT imaging is particularly useful in pre- operative evaluation of patients with aortic valve IE to evaluate coronary artery and aortic involve- ment. In suspected prosthetic valve endocarditis, cardiac CT is less affected by the shadowing of mechanical valves or bioprosthetic valve sew- ing rings than is ultrasonography. CT also allows evaluation of the motion of mechanical valve occluders and provides visualization of throm- bus or infective material limiting valve occluder motion. Additional imaging modalities, such as cardiac valvular fluoroscopy, can be an adjunct to other clinical and imaging information to detect the presence of obstructive disease in mechanical prosthetic valves affected by IE.61,64 68 13. Diagnosis of IE can still be a vexing under- taking. It has been shown that the use of F-fluorodeoxyglucose PET/CT at the initial presentation of patients with suspected pros- thetic valve endocarditis increases the diagnos- tic capability of the Modified Duke Criteria. The inclusion of abnormal 18 F-fluorodeoxyglucose cardiac uptake as a major criterion addition to the Modified Duke Criteria enabled a recatego- rization of 76% of patients with prosthetic valve endocarditis initially classified as possible IE on admission to the hospital to definite IE. This tool must be used in centers with great experi- ence with the technology, as this imaging tech- nique may also be prone to false-positive results because of sterile inflammation in implanted prosthetic valves. 18 F-fluorodeoxyglucose PET/ CT may also be considered a complementary diagnostic tool for some patients with suspected native valve endocarditis.69 71 14. Because the frequency of IE among patients with S. aureus bacteremia is reported to be approxi- mately 30%, with many cases not being clinically suspected, TEE may be considered in the setting of S. aureus bacteremia to rule out IE. Even in S. aureus bacteremia from a known extracardiac source, such as an infected joint or joint prosthe- sis, TEE might be considered, given known cases of seeding of valve tissue in this type of setting. Possible exceptions are patients who have no underlying cardiac predisposing conditions or clinical signs of IE whose fever and bacteremia resolve within 72 hours after removal of a likely CLINICAL STATEMENTS AND GUIDELINES infected focus (such as intravascular catheter removal). In the absence of 1) prolonged bac- teremia lasting >4 days, 2) a permanent intra- cardiac device, 3) hemodialysis dependency, or 4) spinal infection or nonvertebral osteomyelitis, the risk of IE is relatively low, and routine TEE may not be necessary.22,53,54,74 12.3. Medical Therapy Recommendations for Medical Therapy for IE Referenced studies that support the recommendations are summarized in Online Data Supplement 42. COR LOE Recommendations In patients with IE, appropriate antibiotic therapy should be initiated and continued after blood cultures are obtained, with guidance from antibiotic sensitivity data and the infectious disease experts on the MDT.1 7 Patients with suspected or confirmed IE associated with drug use should be referred to addiction treatment for opioid substitution therapy.8 10 In patients with IE and with evidence of cerebral embolism or stroke, regardless of the other indications for anticoagulation, it is reasonable to temporarily discontinue In patients with left-sided IE caused by streptococcus, Enterococcus faecalis, S. aureus, or coagulase-negative staphylococci deemed stable by the MDT after initial intravenous antibiotics, a change to oral antibiotic therapy may be considered if TEE before the switch to oral therapy shows no paravalvular infection, if frequent and appropriate follow-up can be assured by the care team, and if a follow-up TEE can be performed 1 to 3 days before the completion of the antibiotic course.25 In patients receiving VKA anticoagulation at the time of IE diagnosis, temporary discontinuation of VKA anticoagulation may 3: Harm C-LD Patients with known VHD should not receive antibiotics before blood cultures are obtained for unexplained fever.22,35,36 Synopsis Details of specific antimicrobial regimens have been published previously by the AHA, European Society of Cardiology, and British Society for Antimicrobial Che- motherapy and are not repeated in this guideline. In patients on anticoagulant therapy for AF or a mechani- cal heart valve, continued anticoagulation is associated with a higher risk of intracranial bleeding, particularly after an embolic event. In patients with suspected intravenous drug use, effective long-term therapy in- cludes referral to an addiction treatment program. In a select subset of patients with a stable clinical course, it may be possible to convert from intravenous to oral antibiotics if TEE confirms the absence of paravalvu- lar extension of the infection. In addition to antibiotic therapy, early surgical intervention often (approximate- ly 50% of the time) is needed to manage infection and the sequelae of valve leaflet and paravalvular tissue de- struction (Figure 15).1,2,37 42 Recommendation-Specific Supportive Text 1. Optimal treatment of IE is based on the appropri- ately timed initiation of antimicrobial therapy that is effective against the specific infective organ- ism involved. Empirical therapy may be neces- sary in patients with septic shock or patients who show high-risk signs on presentation. Although no RCTs have been performed with regard to the use of antibiotic therapy in IE, the mortality rate before the antibiotic age neared 100%. Specific antimicrobial regimens, depending on the caus- ative microorganism, have been published by the British Society for Antimicrobial Chemotherapy and the AHA. Because there are continuous changes in antimicrobial sensitivity over time, as well as regional and site-specific differences in antimicrobial susceptibility profiles, concomitant management with the assistance of a consul- tant thoroughly familiar with these patterns is 2. Drug use associated endocarditis is associated with a significantly higher complexity of care, with increased rates of readmission, reinfection, and recurrent need for repeat interventions, and its incidence has risen 12-fold over the past decade. Addiction specialists are an important part of the Heart Valve Team for this patient pop- ulation. Addiction studies have shown that treat- ment outcomes for behavioral interventions alone for opioid use disorders are dismal, with >80% of patients returning to drug use. Some data show that patients who used pharmacotherapy, such as agonist therapy (opioid substitution therapy), in addition to behavioral treatments had a 50% reduction in relapse compared with those who used behavioral therapies alone.8 10 3. Stroke in patients with IE can have several mechanisms, including hemorrhagic transfor- mation of an ischemic infarct, septic erosion of an atherosclerotic vessel without aneurysm for- mation, and rupture of a mycotic aneurysm. Up to 35% of all patients with IE develop clinically evident systemic emboli. If more sensitive tests, such as magnetic resonance imaging, are used, a much higher proportion of patients with IE have evidence of emboli. In these patients, the most common cause of stroke is septic embolus CLINICAL STATEMENTS AND GUIDELINES resulting in ischemia, often followed by hemor- rhagic transformation. Anticoagulant therapy may increase the risk of an embolic infarct converting to a hemorrhagic infarct, and this risk must be weighed against the higher risk of recurrent embolization and valve dysfunction, particularly in patients on anticoagulation for a prosthetic valve. A specialist in the field of neu- rology or neuroradiology should be added to the Heart Valve Team when stroke complicates 4. POET randomized stable patients who had left- sided endocarditis caused by streptococcus, E. faecalis, S. aureus, or coagulase-negative staphylococci to treatment arms of contin- ued intravenous treatment or a switch to oral antibiotic treatment after antibiotics had been administered intravenously for at least 10 days. Within 1 to 3 days before the completion of the assigned antibiotic treatment, TEE was per- formed to confirm that the patient had a suf- ficient response to treatment as part of this 5. In patients with native valve endocarditis, rou- tine use of VKA is not recommended. In patients on VKA for other indications who have IE, VKA discontinuation should be considered at the ini- tial presentation for several reasons: 1) the risk of bleeding associated with any needed urgent invasive procedures, 2) the risk of hemorrhagic stroke, and 3) the possible need for early surgery, which is required in roughly 50% of patients with prosthetic valve endocarditis. There are no RCTs studying the use of bridging therapy with intravenous or subcutaneous anticoagulant ther- apy in patients with IE, but observational studies suggest an increased risk of hemorrhagic stroke in patients on intravenous UFH during the acute phase of acute IE. Decisions about continued anticoagulation and antiplatelet therapy should ultimately be directed by the patient s cardiologist and cardiothoracic surgeon, in consultation with a neurology specialist if neurological findings are clinically present or noted on imaging.11,27 34 6. Two sets of blood culture samples are the mini- mum for a secure microbiological diagnosis of IE. Figure 15. Diagnosis of IE. Colors correspond to Table 2. CT indicates computed tomography; IE, infective endocarditis; 18 F-fluorodeoxyglucose; NVE, native valve endocarditis; PET, positron emission tomography; PVE, prosthetic valve endocarditis; TEE, transesophageal echocardiography; and TTE, transthoracic echocardiography. CLINICAL STATEMENTS AND GUIDELINES Recommendations for Intervention for IE (Continued) COR LOE Recommendations Antibiotic therapy is most effective if the identity and sensitivities of the responsible organism are known. S. aureus is the most common pathogen responsible for prosthetic valve endocarditis but still accounts for only 23% of cases. The leading cause of culture-negative IE is the use of antibi- otics before blood cultures are obtained. Negative blood cultures in the setting of IE delay diagnosis and often require additional serological and poly- merase chain reaction testing.22,35,36 Recommendations for Intervention for IE Referenced studies that support the recommendations are summarized in Online Data Supplement 42. COR LOE Recommendations Decisions about the timing of surgical intervention for IE should be made by a Heart In patients with IE who present with valve dysfunction resulting in symptoms of HF, early surgery (during initial hospitalization and before completion of a full therapeutic course of antibiotics) is indicated.7 19 In patients with left-sided IE caused by S. aureus, a fungal organism, or other highly resistant organisms, early surgery (during initial hospitalization and before completion of a full therapeutic course of antibiotics) is In patients with IE complicated by heart block, annular or aortic abscess, or destructive penetrating lesions, early surgery (during initial hospitalization and before completion of a full therapeutic course of antibiotics) is indicated.7,9,36 44 In patients with IE and evidence of persistent infection as manifested by persistent bacteremia or fevers lasting >5 days after onset of appropriate antimicrobial therapy, early surgery (during initial hospitalization and before completion of a full therapeutic course of antibiotics) for IE is indicated.7,9,15,25,26,45 48 In all patients with definite endocarditis and an implanted cardiac electronic device, complete removal of the pacemaker or defibrillator systems, including all leads and the generator, is indicated.49 55 For patients with prosthetic valve endocarditis and relapsing infection (defined as recurrence of bacteremia after a complete course of appropriate antibiotics and subsequent negative blood culture results) without other identifiable source of infection, surgery is In patients with recurrent endocarditis and continued intravenous drug use, consultation with addiction medicine is recommended to discuss the long-term prognosis for the patient s refraining from actions that risk reinfection before repeat surgical intervention In patients with IE who present with recurrent emboli and persistent vegetations despite appropriate antibiotic therapy, early surgery (during initial hospitalization and before completion of a full therapeutic course of antibiotics) is reasonable.53,61 66 In patients with native left-sided valve endocarditis who exhibit mobile vegetations >10 mm in length (with or without clinical evidence of embolic phenomenon), early surgery (during initial hospitalization and before completion of a full therapeutic course of antibiotics) may be In patients with IE and an indication for surgery who have suffered a stroke but have no evidence of intracranial hemorrhage or extensive neurological damage, operation without delay may be considered.68 70 For patients with IE and major ischemic stroke with extensive neurological damage or intracranial hemorrhage, if the patient is hemodynamically stable, delaying valve surgery for at least 4 weeks may be Synopsis Management of patients with IE requires a Heart Valve MDT supplemented by inclusion of infectious disease and neurology specialists. The indications for early surgery for patients with IE include HF, persistent infection, abscess, heart block, infection with highly resistant organisms, or recurrent emboli (with persistent vegetations). In patients with implanted electronic devices, infection of the entire system is likely, even if it appears confined to the leads on imaging, and this mandates removal of the entire system to eradicate the infection. In patients with an indication for early surgery, a cerebral embolic event is not a contra- indication unless there is extensive neurological damage or intracranial hemorrhage (Figure 16). Recommendation-Specific Supportive Text 1. IE is best managed in an environment with ready access to specialists in the fields of cardiology, car- diothoracic surgery, and infectious disease, with the option for transfer of complicated cases to a Comprehensive Valve Center when needed. A risk- scoring system using the STS database has been developed to predict surgical risk in patients with IE to help better counsel patients and more objec- tively define the risks associated with surgery. One trial noted that even when surgery is indicated, women were less likely to undergo a surgical procedure than men (26% versus 47%) and that women had higher in-hospital and 1-year mortality rates than men despite similar comorbidities.1,2,4 6 CLINICAL STATEMENTS AND GUIDELINES 2. Studies have reported a 21% in-hospital mor- tality rate in patients with IE and HF who were treated with surgery versus a 45% mortality rate in those who were treated medically. In left- heart native valve endocarditis, 4 baseline fea- tures have been independently associated with 6-month mortality: 1) abnormal mental status, 2) moderate to severe HF, 3) bacterial etiology other than Viridans streptococci, and 4) medical therapy without valve surgery. Except in inject- able drug users, the risk of reinfection after prosthetic valve surgery is low relative to the risk associated with not having surgery in patients with hemodynamic and microbial indications for surgery. Prosthetic valve endocarditis is clearly associated with both higher mortality rates (especially with HF, severe valvular dysfunction, or a staphylococcal or fungal infectious microbe) and higher post-treatment HF-related disability. Surgical series report surgical rates of 50% in patients with prosthetic valve endocarditis, and these patients show improved outcomes over medical therapy, even with controlling for sever- ity of illness at time of diagnosis.8,9,15 19 3. Compared with patients with IE attributable to other organisms, patients with left-sided S. aureus IE were significantly more likely to die (20% versus 12%), experience an embolic event (60% versus 31%), have a central nervous sys- tem event (20% versus 13%), and not undergo surgery (26% versus 39%). Staphylococcal pros- thetic valve endocarditis has been associated with a mortality rate as high as 70%, which is driven by resistant staphylococcal species. When Staphylococcus is the bacteria, death occurs in <5% of patients with right-sided native valve Figure 16. Endocarditis treatment. Colors correspond to Table 2. *IE caused by streptococcus, E. faecalis, S. aureus, or coagulase-negative staphylococci deemed stable by the Heart Valve Team. Early surgery defined as during initial hospital course and before completion of a full course of appropriate antibiotics. In patients with an indication for surgery and a stroke but no evidence of intracranial hemorrhage or extensive neurological damage, surgery without delay may be considered. DUA indicates drug use as- sociated endocarditis; HF, heart failure; ICD, implantable cardioverter-defibrillator; ID, infectious disease; IE, infective endocarditis; IV, intravenous; NVE, native valve endocarditis; OST, opioid substitution treatment; pt, patient; PVE, prosthetic valve endocarditis; Rx, therapy; S. aureus, Staphylococcus aureus; TEE, transesopha- geal echocardiography; TTE, transthoracic echocardiography; VHD, valvular heart disease; and VKA, vitamin K antagonist. CLINICAL STATEMENTS AND GUIDELINES endocarditis, which is an important distinction in injectable drug users. Certain pathogens, such as Pseudomonas aeruginosa, Brucella, fungi, enterococci, and gram-positive cocci are extremely difficult to cure with medical therapy alone and are also prone to abscess or fistula for- mation and other cardiac tissue destruction. The mortality rate is also significantly lower in patients treated with antifungal agents combined with surgery than in those treated with antifungal agents alone (42% versus 59%).9,15,20,22,28 35 4. Abscess in native valve endocarditis is a life- threatening complication that cannot be cured with antibiotic therapy alone. Extensive para- valvular infections (including annular or aortic abscesses and destructive penetrating lesions or fistulae) are associated with a mortality rate of 40% and heart block. The long-term results of surgery are very satisfactory, with an actuarial survival rate of 75% 6% at 5 years. Freedom from recurrent IE has been reported to be 76% at 8 years. Surgical series have shown that the surgical results are related more to a surgeon s ability to remove all infected tissues and recon- struct functional anatomy than to the type of valve used for a replacement. Patients with prosthetic valve endocarditis complicated by paravalvular invasion, as manifested by intracar- diac abscesses, fistulae, or heart block, experi- ence high mortality rates and are rarely cured by medical treatment alone. By contrast, surgi- cal series have reported surgical survival rates of 71% in this high-risk group.9,41 44 5. Blood culture samples will typically become nega- tive after 48 hours of appropriate antimicrobial therapy, except for with methicillin-resistant S. aureus and other resistant organisms, for which it may take up to a week for cultures to become negative. Some caution is advised in patients who develop recurrent fever after an initially successful response to antibiotics because the fever could be explained by reasons other than the endocarditic valve. Ongoing infection despite antibiotic ther- apy is common with aggressive microorganisms, resulting in abscess formation, valve destruction, fistulas, or large vegetations.7,9,15,46,48 6. Optimal therapy for cardiac device IE combines complete device extraction and a prolonged course of parenteral antibiotics with complete device and lead removal, even if evidence for infection appears to be limited to the generator pocket site. A prospective cohort study using data from the ICE-PCS (International Collaboration on Endocarditis Prospective Cohort Study) showed that among patients with cardiac device IE, the rates of both concomitant valve infection and mortality are high, particularly if there is valve dysfunction. A proportional hazards regression analysis showed a survival benefit at 1 year for device removal during the initial hospitalization; device removal during the index hospitalization had died at 1 year, versus 13 of 34 (38.2%) who did not undergo device removal (HR: 0.42; 95% 7. Relapsing infections may be caused by incom- plete sterilization of valvular or paravalvular tis- sue secondary to a deep tissue infection. Even in the absence of other indications for intervention, such as severe valve dysfunction or a resistant organism, if there is no other source for persis- tent bacteremia, heart valve infection must be presumed to be the source. If the source of infec- tion is uncertain, additional imaging with PET/CT may be helpful in decision-making.7 8. The incidence of drug use associated IE continues to rise, with a known risk of IE that is 100-fold higher than that of the general population. In a National Institutes of Health sponsored state- wide health survey in the state of North Carolina, 42% of all IE valve surgeries performed between 2007 and 2017 were undertaken in patients with injection drug use related IE. The care of these patients is associated with longer hospital stays, higher readmission rates, higher rates of recurrent IE, and higher costs of care. With evolving sci- ence in addiction medicine, there is evidence that referral to addiction therapy can reduce mortality and morbidity rates in these patients. In patients admitted with drug use associated endocarditis, addiction specialists are an integral part of the 9. Embolic events are associated with increased morbidity and mortality in IE and occur in 20% to 40% of patients with IE. The risk of embo- lism is highest during the first days after initia- tion of antibiotic treatment and decreases after 2 weeks. Embolic incidence decreases to 9% to 21% after initiation of antibiotic treatment. Factors associated with a new embolic event are vegetation size >10 mm and marked vegetation mobility (especially when associated with the anterior leaflet of the mitral valve). Early sur- gery is associated with a reduction in the rate of embolic complications in patients who present with left-sided IE, severe VHD, and large vegeta- With native valve endocarditis, large vegetation size is associated with a markedly higher rate of embolic phenomena. In an RCT of surgical intervention in patients with severe left-sided valve dysfunction and vegetations >10 mm in CLINICAL STATEMENTS AND GUIDELINES length (even in the absence of clinically appar- ent embolic events or HF), there was no signifi- cant difference in all-cause mortality rate at 6 months in the early surgery versus the conven- tional treatment groups (3% and 5%, respec- tively; P=0.59); however, there was a marked reduction in the number of embolic events: 0% in the early surgery group compared with 21% in the conventional treatment group (P=0.005). Additionally, 77% of the conventional treat- ment group required surgery during the initial hospitalization or during the follow-up phase secondary to HF, paravalvular extension, and Stroke is an independent risk factor for postoperative death in patients with IE. Recommendations about the timing of opera- tive intervention after a stroke in the setting of IE are hindered by the lack of RCTs and reliance on single-center experiences. In early observa- tional data, there was a significantly decreased risk of in-hospital death when surgery was per- formed >4 weeks after the stroke.73 These data were not risk adjusted. In an observational study that did adjust for factors such as age, para- valvular abscess, and HF, the risk of in-hospital death was not significantly higher in the group who underwent surgery within a median time from admission to operation of 5 days, with only a 1% risk of perioperative hemorrhagic Patients with hemorrhagic stroke and IE have a prohibitively high surgical risk for at least 4 weeks after the hemorrhagic event. One multicenter showed wide variation in patient deaths when those who underwent sur- gery within 4 weeks of a hemorrhagic stroke were compared with those whose surgery was delayed until after 4 weeks (75% versus 40%, respectively). The percentage of new postop- erative bleeds was 50% in patients whose sur- gery was performed in the first 2 weeks, 33% in patients whose surgery was performed in the third week, and 20% in patients whose surgery was performed at least 21 days after the neuro- 13. PREGNANCY AND VHD The physiological hemodynamic changes associated with pregnancy are usually well tolerated in women with structurally normal hearts. However, for women with VHD, the hemodynamic burden may pose signifi- cant challenges during pregnancy and delivery. 13.1. Initial Management of Women With VHD Before and During Pregnancy Recommendations for Initial Management of Women With VHD Before and During Pregnancy Referenced studies that support the recommendations are summarized in Online Data Supplement 43. COR LOE Recommendations Women with suspected valve disease who are considering pregnancy should undergo a clinical evaluation and TTE before pregnancy.1 5 Women with severe valve disease (Stages C and D) who are considering pregnancy should undergo pre-pregnancy counseling by a cardiologist with expertise in managing women with VHD during pregnancy.1 5 Pregnant women with severe valve disease (Stages C and D) should be monitored in a tertiary-care center with a dedicated Heart Valve Team of cardiologists, surgeons, anesthesiologists, and maternal-fetal medicine obstetricians with expertise in the management of high-risk cardiac conditions during pregnancy.1 12 In asymptomatic women with severe valve disease (Stage C1) who are considering pregnancy, exercise testing is reasonable before pregnancy for risk assessment.3 5,11,13 15 Synopsis To assure the best possible outcome for a woman with VHD and her baby, a comprehensive evaluation is best performed before the time of conception. During preg- nancy, the frequency and intensity of follow-up and treatment are heavily dependent on the type and sever- ity of valve lesion, as well as patient symptoms. Recommendation-Specific Supportive Text 1. The risks to the mother and fetus during preg- nancy are highly dependent on the type and sever- ity of valve disease. Clinical evaluation of women with VHD who are contemplating pregnancy includes a complete TTE with full anatomic and hemodynamic assessment of the valves.1 5 A con- genital bicuspid or unicuspid aortic valve is often associated with dilation of the aortic sinuses, the ascending aorta, or both. Evaluation of women with a congenitally abnormal aortic valve includes assessment of the aorta before pregnancy because of the risk of further aortic enlargement and aortic dissection during pregnancy.1 5 2. Pre-pregnancy counseling with a cardiologist expe- rienced with managing women with valve disease during pregnancy allows discussion of the risks of pregnancy for the mother and fetus. A complete assessment of functional capacity, severity of valve lesions, status of the LV and RV, and pulmonary CLINICAL STATEMENTS AND GUIDELINES pressures is necessary to determine the risk of pregnancy and delivery. Medications are reviewed to avoid agents that may have potential harmful effects on the fetus. 