Frequency of Echocardiograms in Asymptomatic Patients With VHD and Normal LV Function Stage Type of Valve Lesion Aortic Stenosis* Aortic Regurgitation Mitral Stenosis Mitral Regurgitation Progressive (Stage B) Every 3 5 y (mild severity; Vmax Every 3 5 y (mild severity) Every 3 5 y (MV area >1.5 ) Every 3 5 y (mild severity) Every 1 2 y moderate severity; Vmax Every 1 2 y (moderate severity) Every 1 2 y (moderate severity) Severe asymptomatic Every 6 12 mo (Vmax 4 m/s) Every 6 12 mo Every 1 2 y (MV area 1.0 ) Every 6 12 mo Dilating LV: More frequently Every year (MV area <1.0 cm2 ) Dilating LV: More frequently Patients with mixed valve disease may require serial evaluations at intervals earlier than recommended for single-valve lesions. These intervals apply to most patients with each valve lesion and do not take into consideration the etiology of the valve disease. *With normal stroke volume. LV indicates left ventricle; MV, mitral valve; VHD, valvular heart disease; and Vmax , maximum velocity. CLINICAL STATEMENTS AND GUIDELINES isolated muscle training may be used to strengthen in- dividual muscle groups. Most patients with LV systolic dysfunction and severe VHD will undergo intervention for the valve itself. However, if intervention is declined or not feasible, standard GDMT drug therapy for LV sys- tolic dysfunction should be continued, including diuret- ics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta blockers, aldosterone antagonists, and/or sacubitril/valsartan and biventricular pacing, as indicated in the guidelines for heart failure (HF).1 In patients with stenotic valve lesions, abrupt lowering of blood pressure should be avoided.1 Rheumatic fever prophylaxis and infective endocardi- tis (IE) prophylaxis should be provided to appropriate groups of patients, as outlined in Sections 2.4.1 and 2.4.2. The maintenance of optimal oral health remains the most important component of an overall healthcare program in preventing IE. Influenza and pneumococcal vaccinations should follow standard recommendations in patients with VHD. For subsets of patients with AF and VHD, anticoagulation is discussed in Section 2.4.3. 2.4.1. Secondary Prevention of Rheumatic Fever Recommendation for Secondary Prevention of Rheumatic Fever COR LOE Recommendation In patients with rheumatic heart disease, secondary prevention of rheumatic fever is indicated (Tables 6 Synopsis Rheumatic fever is an important cause of VHD world- wide, although it is less common in high-income coun- tries. Rapid detection and treatment of streptococcal pharyngitis constitute primary prevention of rheumatic fever. For patients with previous episodes of rheumatic fever or in those with evidence of rheumatic heart dis- ease, long-term antistreptococcal prophylaxis is indicat- ed for secondary prevention.1 Recommendation-Specific Supportive Text 1. Recurrent rheumatic fever is associated with a worsening of rheumatic heart disease. However, infection with group A streptococcus does not have to be symptomatic to trigger a recurrence, and rheumatic fever can recur even when the symptomatic infection is treated. Prevention of recurrent rheumatic fever requires long-term anti- microbial prophylaxis rather than recognition and treatment of acute episodes of group A strepto- coccus pharyngitis. The recommended treatment regimens and duration of secondary prophylaxis are shown in Tables 6 and 7. 2.4.2. IE Prophylaxis Recommendations for IE Prophylaxis Referenced studies that support the recommendations are summarized in Online Data Supplement 1. COR LOE Recommendations Antibiotic prophylaxis is reasonable before dental procedures that involve manipulation of gingival tissue, manipulation of the periapical region of teeth, or perforation of the oral mucosa in patients with VHD who have any of : a. Prosthetic cardiac valves, including transcatheter-implanted prostheses and homografts. b. Prosthetic material used for cardiac valve repair, such as annuloplasty rings, chords, or clips. c. Previous IE. d. Unrepaired cyanotic congenital heart disease or repaired congenital heart disease, with residual shunts or valvular regurgitation at the site of or adjacent to the site of a prosthetic patch or prosthetic device. e. Cardiac transplant with valve regurgitation attributable to a structurally abnormal valve. Benefit B-NR In patients with VHD who are at high risk of IE, antibiotic prophylaxis is not recommended for nondental procedures (eg, TEE, esophagogastroduodenoscopy, colonoscopy, or cystoscopy) in the absence of active Table 6. Secondary Prevention of Rheumatic Fever Antibiotics for Prevention Dosage* Penicillin G benzathine 1.2 million U intramuscularly every 4 wk Penicillin V potassium 200 mg orally twice daily Sulfadiazine 1 g orally once daily Macrolide or azalide antibiotic (for patients allergic to penicillin and sulfadiazine) Varies *In patients with documented valvular heart disease, the duration of rheumatic fever prophylaxis should be 10 y or until the patient is 40 y of age (whichever is longer). Lifelong prophylaxis may be recommended if the patient is at high risk of group A streptococcus exposure. Secondary rheumatic heart disease prophylaxis is required even after valve replacement. Administration every 3 wk is recommended in certain high-risk situations. Macrolide antibiotics should not be used in persons taking other medications that inhibit cytochrome P450 3A, such as azole antifungal agents, HIV protease inhibitors, and some selective serotonin reuptake inhibitors. Adapted from Gerber et al.1 Table 7. Duration of Secondary Prophylaxis for Rheumatic Fever Type Duration After Last Attack* Rheumatic fever with carditis and residual heart disease (persistent VHD ) 10 y or until patient is 40 y of age (whichever is longer) Rheumatic fever with carditis but no residual heart disease (no valvular disease ) 10 y or until patient is 21 y of age (whichever is longer) Rheumatic fever without carditis 5 y or until patient is 21 y of age (whichever is longer) *Lifelong prophylaxis may be recommended if the patient is at high risk of group A streptococcus exposure. Secondary rheumatic heart disease prophylaxis is required even after valve replacement. Clinical or echocardiographic evidence. VHD indicates valvular heart disease. Adapted from Gerber et al.1 CLINICAL STATEMENTS AND GUIDELINES Synopsis With the absence of RCTs addressing the efficacy of anti- biotic prophylaxis for prevention of IE1,12 14 and given un- certainty about which patient populations are at highest risk, these recommendations are based on pathophysio- logical considerations, limited data, and clinical expertise. A prospective study demonstrated that prophylactic anti- biotics given to patients for what is typically considered a high-risk dental procedure reduced but did not eliminate the incidence of bacteremia.2 A 2013 Cochrane Data- base systematic review of antibiotic prophylaxis for the prevention of IE in dentistry concluded that there is no evidence to determine whether antibiotic prophylaxis is effective or ineffective, highlighting the need for further study of this long-standing clinical dilemma.1 Epidemio- logical data conflict with regard to changes in the in- cidence of IE after adoption of more limited antibiotic The consensus of the writing committee is that antibiotic prophylaxis is reasonable for the subset of patients at highest risk of developing IE and at high risk of experiencing adverse outcomes from IE. There is no evidence for IE prophylaxis in gastrointestinal procedures or genitourinary procedures, in the absence of known active infection. Recommendation-Specific Supportive Text 1. The risk of developing IE is highest in patients with a prosthetic valve, prior IE, or congenital heart dis- ease with residual flow disturbances.3 IE has been reported to occur after transcatheter aortic valve implantation (TAVI) at rates equal to or exceeding those associated with surgical aortic valve replace- ment (SAVR) and is associated with a high 1-year mortality rate of 75%.23,24 IE may also occur after valve repair with prosthetic material, which results in high in-hospital and 1-year mortality rates, even with surgical intervention.25,26 IE appears to be more common in heart transplant recipients than in the general population, according to lim- The risk of IE is highest in the first 6 months after transplantation because of endothe- lial disruption, high-intensity immunosuppressive therapy, frequent central venous catheter access, and frequent endomyocardial biopsies.3 Persons at risk of IE can reduce potential sources of bac- terial seeding by maintaining optimal oral health through regular professional dental care and the use of appropriate dental products, such as man- ual, powered, and ultrasonic toothbrushes; dental floss; and other plaque-removal devices. 2. Transient bacteremia is commonly seen in rou- tine activities such as brushing teeth and floss- ing (20% to 68%), using toothpicks (20% to 40%), and simply chewing food (7% to 51%). The incidence of IE after most procedures is low, with no controlled data supporting the benefit of antibiotic prophylaxis. Indiscriminate use of anti- biotics can be associated with the development of resistant organisms, Clostridium difficile colitis, unnecessary expense, and drug toxicity. The rate of transient bacteremia during or immediately after endoscopy is 2% to 5%, and the organisms typically identified are unlikely to cause IE.11,27,28 The rate of bacteremia does not increase with biopsy, polypectomy, or sphincterotomy. Some gastrointestinal procedures are associated with rates of bacteremia higher than that for simple endoscopy; these procedures include esophageal dilation (as high as 45%), sclerotherapy (31%), and endoscopic retrograde cholangiopancreatog- However, no studies have shown reduced rates of IE with antibiotic prophy- laxis. Surgery, instrumentation, or diagnostic pro- cedures that involve the genitourinary tract may cause bacteremia. In the absence of infection, the rate of bacteremia after urinary tract procedures is low. In patients with bacteriuria, antimicrobial therapy before elective procedures, including lith- otripsy, typically is provided.30 2.4.3. Anticoagulation for AF in Patients With VHD Recommendations for Anticoagulation for AF in Patients With VHD Referenced studies that support the recommendations are summarized in Online Data Supplement 2. COR LOE Recommendations For patients with AF and native valve heart disease (except rheumatic mitral stenosis [MS]) or who received a bioprosthetic valve >3 months ago, a non vitamin K oral anticoagulant (NOAC) is an effective alternative to VKA anticoagulation and should be administered on the basis of the patient s CHA2 For patients with AF and rheumatic MS, long-term VKA oral anticoagulation is recommended. For patients with new-onset AF 3 months after surgical or transcatheter bioprosthetic valve replacement, anticoagulation with a VKA 3: Harm B-R In patients with mechanical heart valves with or without AF who require long-term anticoagulation with VKA to prevent valve thrombosis, NOACs are not recommended.7 Synopsis Patients with VHD and AF should be evaluated for risk of thromboembolic events and to treat them with oral anticoagulation if they are at high risk. VKAs are the anticoagulation drugs of choice for patients with rheu- matic MS and mechanical heart valves. NOACs are an alternative to VKAs in patients with AF and 1) with CLINICAL STATEMENTS AND GUIDELINES bioprosthetic valves >3 months after implantation or, 2) with native VHD excluding rheumatic MS (Figure 1). Recommendation-Specific Supportive Text comparing NOACs with war- farin included small numbers of patients with VHD, prior valve repair, and bioprosthetic valves (excluding moderate to severe rheumatic MS and mechanical heart valves). In addition to the examinations of insurance claims data and large registries18 have consistently confirmed no signal for a differen- tial effect between NOAC and VKA therapy.19,20 More consistently observed is a net clinical ben- efit, with fewer events in patients using NOACs than in patients on VKA therapy. Validation of the -VASc risk schema in patients with VHD (excluding moderate to severe rheumatic MS and mechanical heart valves) has been performed in confirming the applicability of this score. Bioprosthetic valves do not appear to be independent predictors of thromboembolic events in patients with AF.19 2. The coexistence of AF and rheumatic MS is com- mon and confers a substantial risk of throm- boembolic events. These patients have been specifically excluded from NOAC trials, yet a single registry study and a US claims database analysis do suggest that NOACs may be poten- These findings need further validation, and currently the use of NOACs can- not be supported over VKA (target international normalized ratio [INR] of 2.5). 3. Postoperative AF after VHD intervention is associated with increased stroke and mortality irrespective of the CHA2 -VASc score. Anticoagulation in this setting may reduce these endpoints. There are conflicting data about the safety and efficacy of NOAC therapy in patients early after implantation of a bioprosthesis.5,6,23 Until more data are available, the writing com- mittee favors using VKA for patients with AF in the first 3 months after surgical or transcath- eter bioprosthetic valve implantation to prevent thromboembolic events. The optimal duration of anticoagulation is not well defined. Repeat evaluation is encouraged in all patients to detect arrhythmia recurrence in the context of their -VASc scores. 4. The phase II study comparing dabigatran to warfarin (RE-ALIGN [Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement]) was halted prematurely because of excess stroke and Figure 1. Anticoagulation for AF in Patients With VHD. Colors correspond to Table 2. AF indicates atrial fibrillation; MS, mitral stenosis; NOAC, non vitamin K oral anticoagulant; VHD, valvular heart disease; and VKA, vitamin K antagonist. CLINICAL STATEMENTS AND GUIDELINES bleeding in the dabigatran group. Until there is an explanation of why these adverse events occurred, there is insufficient evidence to support the use of NOACs for patients with mechanical heart valves.7 2.5. Evaluation of Surgical and Interventional Risk Recommendation for Evaluation of Surgical and Interventional Risk COR LOE Recommendation For patients with VHD for whom intervention is contemplated, individual risks should be calculated for specific surgical and/or transcatheter procedures, using online tools when available, and discussed before the procedure as a part of a shared decision-making process. Synopsis Risk assessment has become a foundational element of the preprocedural evaluation of patients with VHD for whom intervention to correct the valve lesion may be contemplated. Although there are limitations to the scoring systems used to estimate the risk of adverse outcomes, these estimates provide a useful point of reference against which procedural benefits can be weighed. Numerical estimates of risk are just one com- ponent of the multidisciplinary team (MDT) assessment process, and factors not routinely included in risk algo- rithms (eg, liver disease, porcelain aorta) add important dimensions. The availability of TAVI for treatment of symptomatic severe aortic stenosis (AS) across the sur- gical risk spectrum emphasizes the need to have discus- sions about younger age at implantation, valve durabil- ity, and the potential need for permanent pacemaker implantation. For young patients (eg, <65 years of age) who opt for a surgical bioprosthesis, strategies for se- quential procedures over a longer follow-up period (ie, valve-in-valve [ViV] TAVI versus reoperation) must be addressed. Recommendation-Specific Supportive Text 1. The decision to intervene, as well as the type of procedure recommended, is based on an assess- ment of patient-, procedure-, and institution- or operator-specific short-term risks and long-term benefits (Table 8). Surgical mortality rate and major morbidity risks can be calculated with a web- based tool derived from the Society of Thoracic Surgeons (STS) Adult Cardiac Surgery database for 6 specific procedures (http://riskcalc.sts.org/ stswebriskcalc/calculate). TAVI-specific risk predic- tion tools are also available (http://tools.acc.org/ Frailty assess- ment for at-risk patients is routine.7 11 Patients toward the higher end of the risk spectrum, for whom intervention would be futile or associated with a high likelihood of a poor outcome, should Table 8. Risk Assessment for Surgical Valve Procedures Criteria Low-Risk SAVR (Must Meet ALL Criteria in This Column) Low-Risk Surgical Mitral Valve Repair for Primary MR (Must Meet ALL Criteria in This Column) High Surgical Risk (Any 1 Criterion in This Column) Prohibitive Surgical Risk (Any 1 Criterion in This Column) STS-predicted risk of death* AND AND OR Predicted risk of death or major morbidity (all-cause) >50% at 1 y OR Frailty None AND None AND 2 Indices (moderate to severe) OR 2 Indices (moderate to severe) OR Cardiac or other major organ system compromise not to be improved postoperatively None AND None AND 1 to 2 Organ systems OR 3 Organ systems OR Procedure-specific impediment None None Possible procedure-specific impediment Severe procedure-specific impediment *Use of the STS Predicted Risk of Mortality (http://riskcalc.sts.org/stswebriskcalc/#/) to predict risk in a given institution with reasonable reliability is appropriate only if institutional outcomes are within 1 standard deviation of the STS average observed/expected mortality ratio for the procedure in question. The EUROSCORE II risk calculator may also be considered for use and is available at http://www.euroscore.org/calc.html. Seven frailty indices: Katz Activities of Daily Living (independence in feeding, bathing, dressing, transferring, toileting, and urinary continence) plus independence in ambulation (no walking aid or assistance required, or completion of a 5-m walk in <6 s). Other scoring systems can be applied to calculate no, mild, or moderate to severe frailty. Examples of major organ system compromise include cardiac dysfunction (severe LV systolic or diastolic dysfunction or RV dysfunction, fixed pulmonary hypertension); kidney dysfunction (chronic kidney disease, stage 3 or worse); pulmonary dysfunction (FEV1 <50% of predicted); central nervous system dysfunction (dementia, Alzheimer s disease, Parkinson s disease, cerebrovascular accident with persistent physical limitation); gastrointestinal dysfunction (Crohn s disease, ulcerative colitis, nutritional impairment, or serum albumin <3.0); cancer (active malignancy); and liver dysfunction (any history of cirrhosis, variceal bleeding, or elevated INR in the absence of VKA therapy). Examples of procedure-specific impediments include presence of tracheostomy, heavily calcified (porcelain) ascending aorta, chest malformation, arterial coronary graft adherent to posterior chest wall, and radiation damage. indicates diffusion capacity for carbon dioxide; FEV1 , forced expiratory volume in 1 s; INR, international normalized ratio; LV, left ventricular; MR, mitral regurgitation; RV, right ventricular; SAVR, surgical aortic valve replacement; STS, Society of Thoracic Surgeons; and VKA, vitamin K antagonist. CLINICAL STATEMENTS AND GUIDELINES Risk prediction tools for trans- catheter mitral valve repair are comparatively less The relationship between operator/ institutional case volume and outcomes has been explored for surgical20 aor- tic valve replacement (AVR), surgical mitral valve repair and replacement,24 32 and transcatheter mitral valve repair.33 Table 9 includes examples of several factors that impact outcomes but are not routinely captured in currently available risk scores. Perioperative mortality rates for 6 specific surgical procedures are shown in Table 10. The potential to return to activities of daily living after an intervention must be considered. 2.6. The Multidisciplinary Heart Valve Team and Heart Valve Centers Recommendations for the Multidisciplinary Heart Valve Team and Heart Valve Centers COR LOE Recommendations Patients with severe VHD should be evaluated by a Multidisciplinary Heart Valve Team (MDT) when intervention is considered. Consultation with or referral to a Primary or Comprehensive Heart Valve Center is reasonable when treatment options are being discussed for 1) asymptomatic patients with severe VHD, 2) patients who may benefit from valve repair versus valve replacement, or 3) patients with multiple comorbidities for whom valve intervention is considered.1 19 Synopsis The value of the MDT has become increasingly appar- ent as options in the treatment of VHD have broad- ened. Heart Valve Centers, in the context of an inte- grated multi-institutional model of care for patients with VHD, allow optimization of patient outcomes through improved decision-making and matching of patients to providers with appropriate expertise, expe- rience, and resources.12 Primary and Comprehensive Heart Valve Centers are defined by their offerings and expertise in the management of patients with VHD12 (Table 11). Table 9. Examples of Procedure-Specific Risk Factors for Interventions Not Incorporated Into Existing Risk Scores SAVR TAVI Surgical Mitral Valve Repair or Replacement TEER Technical or anatomic Prior mediastinal radiation Aorto-iliac occlusive disease precluding transfemoral approach Prior sternotomy Multivalve disease Ascending aortic calcification (porcelain aorta may be prohibitive) Aortic arch atherosclerosis (protuberant lesions) Severe MR or TR Low-lying coronary arteries Basal septal hypertrophy Valve morphology (eg, bicuspid or unicuspid valve) Extensive LV outflow tract calcification Prior mediastinal radiation Ascending aortic calcification (porcelain aorta may be prohibitive) Valve morphology (eg, thickening, perforations, clefts, calcification, and stenosis) Prior mitral valve surgery Comorbidities Severe COPD or home oxygen therapy Pulmonary hypertension Severe RV dysfunction Hepatic dysfunction Frailty* Severe COPD or home oxygen therapy Pulmonary hypertension Severe RV dysfunction Hepatic dysfunction Frailty* Severe COPD or home oxygen therapy Pulmonary hypertension Hepatic dysfunction Frailty* Severe COPD or home oxygen therapy Pulmonary hypertension Hepatic dysfunction Frailty* Futility STS score >15 Life expectancy <1 y Poor candidate for rehabilitation STS score >15 Life expectancy <1 y Poor candidate for rehabilitation STS score >15 Life expectancy <1 y Poor candidate for rehabilitation STS score >15 Life expectancy <1 y Poor candidate for rehabilitation *Validated frailty scores include the Katz Activities of Daily Living Score.10,34,35 COPD indicates chronic obstructive pulmonary disease; MR, mitral regurgitation; RV, right ventricular; SAVR, surgical aortic valve replacement; STS, Society of Thoracic Surgeons; TAVI, transcatheter aortic valve implantation; TEER, transcatheter edge-to-edge repair; and TR, tricuspid regurgitation. Table 10. Median Operative Mortality Rates for Specific Surgical Procedures (STS Adult Cardiac Surgery Database, 2019) Procedure Mortality Rate (%) AVR and CABG 4 AVR and mitral valve replacement 9 Mitral valve replacement 5 Mitral valve replacement and CABG 9 Mitral valve repair 1 Mitral valve repair and CABG 5 AVR indicates aortic valve replacement; CABG, coronary artery bypass graft surgery; and STS, Society of Thoracic Surgeons. CLINICAL STATEMENTS AND GUIDELINES Table 11. Structure of Primary and Comprehensive Valve Centers Comprehensive (Level I) Valve Center Primary (Level II) Valve Center Interventional procedures* TAVI transfemoral TAVI transfemoral Percutaneous aortic valve balloon dilation Percutaneous aortic valve balloon dilation TAVI alternative access, including transthoracic (transaortic, transapical) and extrathoracic (eg, subclavian, carotid, caval) approaches Valve-in-valve procedures TEER Prosthetic valve paravalvular leak closure Percutaneous mitral balloon commissurotomy Surgical procedures* SAVR SAVR Valve-sparing aortic root procedures Aortic root procedures for aneurysmal disease Concomitant septal myectomy with AVR Root enlargement with AVR Mitral repair for primary MR Mitral repair for posterior leaflet primary MR Mitral valve replacement Mitral valve replacement Multivalve operations Reoperative valve surgery Isolated or concomitant tricuspid valve repair or replacement Concomitant tricuspid valve repair or replacement with mitral surgery Imaging personnel Echocardiographer with expertise in valve disease and transcatheter and surgical interventions Echocardiographer with expertise in valve disease and transcatheter and surgical interventions Expertise in CT with application to valve assessment and procedural planning Expertise in CT with application to valve assessment and procedural planning Interventional echocardiographer to provide imaging guidance for transcatheter and intraoperative procedures Expertise in cardiac MRI with application to assessment of VHD Criteria for imaging personnel A formalized role/position for a valve echocardiographer who performs both the pre- and postprocedural assessment of valve disease A formalized role/position for a valve echocardiographer who performs both the pre- and postprocedural assessment of valve disease A formalized role/position for the expert in CT who oversees the preprocedural assessment of patients with valve disease A formalized role/position for the expert in CT who oversees the preprocedural assessment of patients with valve disease A formalized role/position for an interventional echocardiographer Institutional facilities and infrastructure MDT MDT A formalized role/position for a dedicated valve coordinator who organizes care across the continuum and system of care A formalized role/position for a dedicated valve coordinator who organizes care across the continuum and system of care Cardiac anesthesia support Cardiac anesthesia support Palliative care team Palliative care team Vascular surgery support Vascular surgery support Neurology stroke team Neurology stroke team Consultative services with other cardiovascular subspecialties Consultative services with other medical and surgical subspecialties Echocardiography 3D TEE; comprehensive TTE for assessment of valve disease Echocardiography comprehensive TTE for assessment of valve disease Cardiac CT Cardiac CT ICU ICU (Continued) CLINICAL STATEMENTS AND GUIDELINES Recommendation-Specific Supportive Text 1. The MDT is an established feature of heart valve and has been formally endorsed by the ACC, the American Society of Echocardiography, the Society for Cardiovascular Angiography and Interventions, the American Association for Thoracic Surgery, and the STS.12 Key members of the MDT include cardiologists with subspecialty expertise in the clinical evaluation of patients with VHD, as well as specialists in advanced cardiovas- cular imaging. For the evaluation of the patient with secondary mitral regurgitation (MR) and tri- cuspid regurgitation (TR), a specialist in HF also is included. Interventional cardiologists with training and expertise in VHD and surgeons experienced in the treatment of VHD anchor the MDT. Other team members include cardiovascular nurses, cardiovas- cular anesthesiologists, and intensivists involved in periprocedural care. Finally, the engagement of the primary clinical cardiologist and patient is of critical importance. The MDT facilitates presenta- tion of all appropriate options for medical, inter- ventional, and surgical treatment to the patient in a balanced manner, using tools and techniques for shared decision-making in which patient prefer- ences are considered. 2. Decision-making is particularly challenging for the asymptomatic VHD patient, for whom the risks of operative mortality and perioperative morbidity must be very low and the chances of a successful and durable surgical outcome very high. There is a substantial body of literature to support a relationship between institutional vol- ume and mortality rate for many cardiovascular procedures, including SAVR,1 5 and surgi- cal mitral valve repair.7 11 Consideration should be given to consultation with or referral to a Primary or Comprehensive Heart Valve Center for asymp- tomatic patients with severe VHD. Although excellent outcomes certainly can be achieved at lower-volume centers, assurance of outcomes equivalent to those of a higher-volume center is statistically more challenging.12 Similarly, for patients with multiple comorbidities for whom multispecialty collaboration is anticipated, care at a Comprehensive or Primary Valve Center ensures optimal outcomes. Although findings are mixed,13 there are data to support relationships between center volume and complication rates in cardiac between center volume and fail- ure to rescue after procedural complications,15 17 and between center volume and elements of 2.7. Management of Patients With VHD After Valve Intervention Interventions in patients with VHD include both trans- catheter and surgical approaches. A valve interven- tion leaves the patient with either a prosthetic valve or a valve repair, often with an implanted device or other prosthetic material. Valve intervention does not eliminate valve disease; it replaces native valve disease with palliated valve disease. Patients with VHD con- tinue to require periodic evaluation after intervention Temporary mechanical support (including percutaneous support devices such as intra-aortic balloon counterpulsation, temporary percutaneous ventricular assist device or ECMO) Temporary mechanical support (including percutaneous support devices such as intra-aortic balloon counterpulsation, temporary percutaneous ventricular assist device or ECMO) Left/right ventricular assist device capabilities (on-site or at an affiliated institution) Cardiac catheterization laboratory, hybrid catheterization laboratory, or hybrid OR laboratory Cardiac catheterization laboratory PPM and ICD implantation PPM and ICD implantation Criteria for institutional facilities and infrastructure IAC echocardiography laboratory accreditation IAC echocardiography laboratory accreditation 24/7 intensivist coverage for ICU *A primary (Level II) Center may provide additional procedures traditionally offered at a Comprehensive (Level I) Center as long as the criteria for competence and outcomes are met. If intraoperative imaging and surgical expertise exist. If mitral valve anatomy is not suitable for valve repair. Equipped with a fixed radiographic imaging system and flat-panel fluoroscopy, offering catheterization laboratory-quality imaging and hemodynamic capability. AVR indicates aortic valve replacement; CT, computed tomography; ECMO, extracorporeal membrane oxygenation; ICD, implantable cardioverter defibrillator; IAC, Intersocietal Accreditation Commission; ICU, intensive care unit; MDT, multidisciplinary team; MR, mitral regurgitation; MRI, magnetic resonance imaging; OR operating room; PPM, permanent pacemaker; SAVR, surgical aortic valve replacement; TAVI, transcatheter aortic valve implantation; TEE, transesophageal echocardiography; TEER, transcatheter edge-to-edge repair; TTE, transthoracic echocardiography; VHD, valvular heart disease; and ViV, valve-in-valve. Used with permission from Nishimura et al.12 Table 11. Continued Comprehensive (Level I) Valve Center Primary (Level II) Valve Center CLINICAL STATEMENTS AND GUIDELINES for early postprocedural issues, long-term medical therapy, monitoring of the prosthetic valve or repair, management of concurrent cardiac conditions, and persistent symptoms or functional limitation. Endo- carditis prophylaxis is discussed in Section 2.4.2; an- tithrombotic therapy for prosthetic valves in Sections 11.2 to 11.5; and prosthetic valve complications, in- cluding valve thrombosis, stenosis, or regurgitation, in Sections 11.6 to 11.8. 2.7.1. Procedural Complications The most common complication early after surgical valve replacement is postoperative AF, which occurs in up to one-third of patients within 3 months of sur- gery (see Sections 2.4.3 and 14.1). Other complications include stroke, vascular and bleeding complications, pericarditis, heart block requiring temporary or perma- nent pacing (especially after AVR), HF, renal dysfunc- tion, and infection. Complications after transcatheter interventions depend on the specific procedure but can include the need for permanent pacing, paravalvular leak, stroke, vascular complications, and residual valve dysfunction. 2.7.2. Primary and Secondary Risk Factor Evaluation and Treatment Concurrent coronary artery disease (CAD) is common in adults with VHD. Management of CAD at the time of valve intervention is discussed in Section 14.2. Af- ter valve intervention, evaluate and treat patients with CAD risk factors according to current guidelines for primary and secondary prevention. Although there is no convincing evidence that treating CAD risk factors will reduce the likelihood of progressive valve dysfunc- tion after intervention, cardiovascular outcomes are im- proved overall because of a reduced rate of coronary events. 2.7.3. Persistent Symptoms After Valve Intervention Persistent symptoms occur in many patients after valve intervention. The first step in evaluation is to as- sess valve function to ensure symptoms are not caused by persistent or recurrent stenosis, regurgitation, or a valve complication. The next step is to evaluate and treat any concurrent cardiac disease and noncardiac conditions that may be the cause of symptoms. Symp- toms also may be attributable to irreversible conse- quences of valve disease, including LV systolic and diastolic dysfunction, pulmonary hypertension, and RV dysfunction. Treatment of symptoms for these pa- tients is based on GDMT for HF and/or pulmonary hy- pertension. 2.7.4. Periodic Imaging After Valve Intervention Recommendation for Periodic Imaging After Valve Intervention COR LOE Recommendation In asymptomatic patients with any type of valve intervention, a baseline postprocedural TTE followed by periodic monitoring with TTE is recommended, depending on type of intervention, length of time after intervention, ventricular function, and concurrent cardiac conditions. Synopsis A TTE is useful after either catheter-based or surgi- cal intervention to provide a baseline measurement of valve function and the status of the ventricle. Repeat TTE is recommended with either new symptoms or a change in the physical examination. The timing of pe- riodic follow-up imaging is based on the type of valve intervention. Table 12. Timing of Periodic Imaging After Valve Intervention Valve Intervention Imaging Follow-Up* Minimal Imaging Frequency Location Mechanical valve (surgical) Baseline Primary Valve Center Bioprosthetic valve (surgical) Baseline, 5 and 10 y after surgery, and then annually Primary Valve Center Bioprosthetic valve (transcatheter) Baseline and then annually Primary Valve Center Mitral valve repair (surgical) Baseline, 1 y, and then every 2 to 3 y Primary Valve Center Mitral valve repair (transcatheter) Baseline and then annually Comprehensive Valve Center Bicuspid aortic valve disease Continued post-AVR monitoring of aortic size if aortic diameter is 4.0 cm at time of AVR, as detailed in Section 5.1 Primary Valve Center *Initial postprocedural TTE is recommended for all patients, ideally 1 to 3 months after the procedure. Annual clinical follow-up is recommended annually for all patients after valve intervention at a Primary or Comprehensive Valve Center. Repeat imaging is appropriate at shorter follow-up intervals for changing signs or symptoms, during pregnancy, and to monitor residual or concurrent cardiac dysfunction. Imaging may be done more frequently in patients with bioprosthetic surgical valves if there are risk factors for early valve degeneration (eg, younger age, renal failure, diabetes). AVR indicates aortic valve replacement; and TTE, transthoracic echocardiography. CLINICAL STATEMENTS AND GUIDELINES Recommendation-Specific Supportive Text 1. In patients who have had a valve intervention, most cardiologists continue to see patients for a clinical history and physical examination at annual intervals, or more frequently if needed for symptoms or concurrent conditions. A baseline TTE study is recommended after all valve inter- ventions, including replacement with a prosthetic valve (see Section 11.1). This baseline postproce- dural study ideally is performed 1 to 3 months after intervention to ensure loading conditions have returned to normal, but in some cases it may need to be done during the index hospital- ization for the patient s convenience. The tim- ing of subsequent periodic imaging after valve intervention is based on the type of valve pros- thesis or repair, length of time after valve inter- vention, residual valve dysfunction, ventricular size and systolic function, and any concurrent cardiac conditions (Table 12). TTE is the standard approach for periodic imaging, supplemented by TEE when prosthetic mitral valve dysfunction is a concern (see Section 11.1). Additional imaging with CT, fluoroscopy CMR, or PET is reserved for patients for whom there is concern about valve dysfunction (see Section 11.1) or endocarditis (see Section 12.1).1,2 3. AORTIC STENOSIS 3.1. Stages of Valvular AS Medical and interventional approaches to the manage- ment of patients with valvular AS depend on accurate diagnosis of the cause and stage of the disease process. Table 13 shows the stages of AS, ranging from patients at risk of AS (Stage A) or with progressive hemody- namic obstruction (Stage B) to severe asymptomatic (Stage C) and symptomatic AS (Stage D). Each stage is defined by patient symptoms, valve anatomy, valve hemodynamics, and changes in the LV and vascula- ture. Hemodynamic severity is best characterized by the transaortic maximum velocity (or mean pressure gradi- ent) when the transaortic volume flow rate is normal. Some patients with AS have a low transaortic volume flow rate that is either because of LV systolic dysfunc- tion with a low LVEF or because of a small, hypertro- phied LV with a low stroke volume. Severe AS with low flow is designated D2 (with a low LVEF) or D3 (with a normal LVEF). Meticulous attention to detail is required during assessment of aortic valve hemodynamics, either with Doppler echocardiography or cardiac catheteriza- tion, and the inherent variability of the measurements and calculations should always be considered in clinical decision-making. 3.2. Aortic Stenosis 3.2.1. Diagnosis and Follow-Up 3.2.1.1. Diagnostic Testing: Initial Diagnosis Recommendations for Diagnostic Testing: Initial Diagnosis of AS Referenced studies that support the recommendations are summarized in Online Data Supplement 3. COR LOE Recommendations In patients with signs or symptoms of AS or a BAV, TTE is indicated for accurate diagnosis of the cause of AS, assessment of hemodynamic severity, measurement of LV size and systolic function, and determination of prognosis and timing of valve intervention.1,2 In patients with suspected low-flow, low- gradient severe AS with normal LVEF (Stage D3), optimization of blood pressure control is recommended before measurement of AS severity by TTE, TEE, cardiac catheterization, In patients with suspected low-flow, low- gradient severe AS with reduced LVEF (Stage D2), low-dose dobutamine stress testing with echocardiographic or invasive hemodynamic measurements is reasonable to further define severity and assess In patients with suspected low-flow, low- gradient severe AS with normal or reduced LVEF (Stages D2 and D3), calculation of the ratio of the outflow tract to aortic velocity is reasonable to further define severity.1,11 13 In patients with suspected low-flow, low- gradient severe AS with normal or reduced LVEF (Stages D2 and D3), measurement of aortic valve calcium score by CT imaging is reasonable to further define severity.14 18 Synopsis The overall approach to the initial diagnosis of VHD is discussed in Section 2.3, and additional consid- erations specific to patients with AS are addressed here. Recommendation-Specific Supportive Text 1. In adult patients, physical examination may not be accurate for diagnosis of and assessment of severity of AS. Echocardiographic imaging allows reliable evaluation of valve anatomy and motion and the degree of valve obstruction. In addition, TTE is useful for measuring LV size and systolic function, identifying concurrent AR or MR, and estimating pulmonary systolic 2. Measurements of AS severity made when the patient is hypertensive may underestimate or, less often, overestimate stenosis severity. Systemic hypertension imposes a second pressure load on the LV, in addition to valve obstruction, which CLINICAL STATEMENTS AND GUIDELINES results in a lower forward stroke volume and lower transaortic pressure gradient than when the patient is normotensive. Thus, Doppler veloc- ity data and invasive pressure measurements ideally are recorded when the patient is normo- tensive. If results indicate only moderate stenosis but were recorded when the patient was hyper- tensive, repeat measurements when the blood pressure is better controlled ensure that a diag- nosis of severe AS is not missed. 3. Patients with severe AS and LVEF <50% present with an aortic valve area <1.0 cm2 but a low transvalvular velocity and pressure gradient (ie, velocity <4 m/s or mean gradient <40 mm Hg) at rest. In these patients, severe AS with LV systolic dysfunction attributable to afterload Table 13. Stages of AS Stage Definition Valve Anatomy Valve Hemodynamics Hemodynamic Consequences Symptoms A At risk of AS BAV (or other congenital valve anomaly) Aortic valve sclerosis Aortic Vmax <2 m/s with normal leaflet motion None None B Progressive AS Mild to moderate leaflet calcification/fibrosis of a bicuspid or trileaflet valve with some reduction in systolic motion or Rheumatic valve changes with commissural fusion Mild AS: aortic Vmax m/s or mean P <20 mm Hg Moderate AS: aortic Vmax 3.0 3.9 m/s or mean P 20 39 mm Hg Early LV diastolic dysfunction may be present Normal LVEF None C: Asymptomatic severe AS C1 Asymptomatic severe AS Severe leaflet calcification/ fibrosis or congenital stenosis with severely reduced leaflet opening Aortic Vmax 4 m/s or mean P 40 mm Hg AVA typically is 1.0 cm2 (or ) but not required to define severe AS Very severe AS is an aortic Vmax 5 m/s or mean P 60 mm Hg LV diastolic dysfunction Mild LV hypertrophy Normal LVEF None Exercise testing is reasonable to confirm symptom status C2 Asymptomatic severe AS with LV systolic dysfunction Severe leaflet calcification/ fibrosis or congenital stenosis with severely reduced leaflet opening Aortic Vmax 4 m/s or mean P 40 mm Hg (or ) but not required to define severe AS LVEF <50% None D: Symptomatic severe AS D1 Symptomatic severe high-gradient AS Severe leaflet calcification/ fibrosis or congenital stenosis with severely reduced leaflet opening Aortic Vmax 4 m/s or mean P 40 mm Hg (or ) but may be larger with mixed AS/AR LV diastolic dysfunction LV hypertrophy Pulmonary hypertension may be present Exertional dyspnea, decreased exercise tolerance, or HF Exertional angina Exertional syncope or presyncope D2 Symptomatic severe low-flow, low-gradient AS with reduced LVEF Severe leaflet calcification/ fibrosis with severely reduced leaflet motion with resting aortic Vmax <4 m/s or mean P <40 mm Hg Dobutamine stress echocardiography shows with Vmax m/s at any flow rate LV diastolic dysfunction LV hypertrophy HF Angina Syncope or presyncope D3 Symptomatic severe low-gradient AS with normal LVEF or paradoxical low-flow severe AS Severe leaflet calcification/ fibrosis with severely reduced leaflet motion (indexed AVA ) with an aortic Vmax <4 m/s or mean P <40 mm Hg AND Stroke volume index <35 Measured when patient is normotensive (systolic blood pressure <140 mm Hg) Increased LV relative wall thickness Small LV chamber with low stroke volume Restrictive diastolic filling HF Angina Syncope or presyncope AR indicates aortic regurgitation; AS, aortic stenosis; AVA, aortic valve area circulation; AVAi, AVA indexed to body surface area; BAV, bicuspid aortic valve; P, pressure gradient between the LV and aorta HF, heart failure; LV, left ventricular; LVEF, left ventricular ejection fraction; and Vmax , maximum velocity. CLINICAL STATEMENTS AND GUIDELINES mismatch must be distinguished from primary myocardial dysfunction with only moderate AS. Dobutamine stress echocardiography may be useful with measurement of aortic velocity (or mean pressure gradient) and valve area at baseline and at higher flow rates (maximum dose dobutamine 20 mcg/kg per minute) under appropriate clinical and hemodynamic moni- toring. Severe AS is characterized by a fixed valve area, resulting in an increase in trans- aortic velocity to 4 m/s (mean gradient 40 mm Hg) at any flow rate, but with valve area . In contrast, in patients with moderate AS and primary LV dysfunction, there is an increase in valve area as volume flow rate increases, resulting in only a mod- est increase in transaortic velocity or gradient. Some patients fail to show an increase in stroke volume 20% with dobutamine, referred to as lack of contractile reserve or lack of flow 4. The key measurements for clinical decision-mak- ing in patients with AS are the maximum aortic velocity, mean pressure gradient (calculated with the Bernoulli equation), and valve area (calculated with the continuity equation). An additional mea- surement that may be useful when there are dis- crepancies in these measures or in other clinical or imaging data is the ratio of the velocity in the LV outflow tract proximal to the aortic valve and the velocity in the narrowed aortic orifice. The outflow tract to aortic velocity ratio is indepen- dent of body size and eliminates potential errors in calculated valve area related to measurement of LV outflow tract diameter or area. A normal ratio is close to 1.0, whereas a ratio of 0.25 corresponds to a valve area 25% of normal for that patient, which is consistent with severe AS and is a predictor of symptom onset and adverse 5. The degree of aortic valve calcification is a strong predictor of clinical outcome, even when evaluated qualitatively by echocardiography.33 Quantitation of aortic valve calcium by CT imag- ing is especially useful in patients with low-flow, low-gradient AS of unclear severity with either a normal or reduced LVEF. Sex-specific Agaston unit thresholds for diagnosis of severe AS are 1300 in women and 2000 in men. These differ- ent thresholds reflect the contribution of leaflet fibrosis, in addition to calcification, to increased leaflet stiffness in women. CT imaging also is used for procedural planning in patients under- going TAVI, for measurement of annulus area, leaflet length, and the annular to coronary 3.2.1.2. Diagnostic Testing: Changing Signs or Symptoms In patients with known valvular AS, repeat TTE is pru- dent when physical examination shows an increase in the loudness of the murmur, the murmur peaks later in systole, the A2 component of the second heart sound is diminished or absent, or symptoms occur that might be attributable to AS. Repeat TTE is also appropriate in patients with AS who are exposed to increased hemo- dynamic demands, either electively, such as with non- cardiac surgery or pregnancy, or acutely, such as with a systemic infection, anemia, or gastrointestinal bleeding. In these clinical settings, knowledge of the severity of valve obstruction and LV function is critical for optimiz- ing loading conditions and maintaining a normal car- diac output. 3.2.1.3. Diagnostic Testing: Routine Follow-Up Timing of periodic clinical evaluation of asymptomatic patients with severe AS depends on comorbidities and patient-specific factors, as well as AS severity (Table 4). When severe AS is present (aortic velocity 4.0 m/s), the rate of progression to symptoms is high, with an event-free survival rate of only 30% to 50% at 2 years. In patients with asymptomatic severe AS, peri- odic monitoring is needed because symptom onset is insidious and may not be recognized by the patient. With moderate AS (aortic velocity 3.0 3.9 m/s), the average annual rate of progression is an increase in ve- locity of 0.3 m/s, increase in mean pressure gradient of 7 mmHg, and decrease in valve area of 0.1 cm2 . There is marked individual variability, with more rapid progression in older patients and in patients with more severe leaflet calcification. In patients with aortic scle- rosis, defined as focal areas of valve calcification and leaflet thickening with an aortic velocity <2.0 m/s, pro- gression to severe AS occurs in about 10% of patients within 5 years. Patients with BAV disease are also at risk of progressive valve stenosis, with AS being the most common reason for intervention in patients with a BAV (Section 5.1.1).1 13 3.2.1.4. Diagnostic Testing: Cardiac Catheterization Diagnostic TTE and Doppler data can be obtained in nearly all patients, but severity of AS may be underes- timated if image quality is poor or if a parallel intercept angle is not obtained between the ultrasound beam and aortic jet. When data from noninvasive testing are non- diagnostic or if there is a discrepancy between clinical and echocardiographic evaluation, cardiac catheteriza- tion for determination of severity of AS can be helpful. Transaortic pressure gradient recordings allow measure- ment of the mean transaortic gradient via simultaneous LV and aortic pressure measurements. Aortic valve area CLINICAL STATEMENTS AND GUIDELINES is calculated with the Gorlin formula by using a Fick or thermodilution cardiac output measurement. See Sec- tion 14.1 for recommendations on coronary angiogra- phy in patients with AS.1,2 3.2.1.5. Diagnostic Testing: Exercise Testing Recommendations for Diagnostic Testing: Exercise Testing in Patients With AS Referenced studies that support the recommendations are summarized in Online Data Supplement 4. COR LOE Recommendations In asymptomatic patients with severe AS (Stage C1), exercise testing is reasonable to assess physiological changes with exercise and to confirm the absence of 3: Harm B-NR In symptomatic patients with severe AS (Stage D1, aortic velocity 4.0 m/s or mean pressure gradient 40 mmHg), exercise testing should not be performed because of the risk of severe Synopsis In a subset of asymptomatic patients with severe AS, exercise testing can provide additional diagnostic and prognostic information, but it should not be performed in symptomatic patients with severe AS. Recommendation-Specific Supportive Text 1. When performed under the direct supervision of an experienced clinician, with close monitoring of blood pressure and ECG, exercise testing in asymp- tomatic patients is relatively safe and may provide information that is not evident during the initial clinical evaluation, particularly when the patient s functional capacity is unclear. Patients with symp- toms provoked by exercise testing should be con- sidered symptomatic, even if the clinical history is equivocal. Although it can be challenging to sep- arate normal exercise limitations from abnormal symptoms that are attributable to AS, particularly in elderly sedentary patients, exercise-induced angina, excessive dyspnea early in exercise, dizzi- ness, and syncope are consistent with symptoms of AS. Exercise testing can also identify a limited exercise capacity or an abnormal blood pressure response. Recording aortic valve hemodynam- ics with exercise is of limited value and does not show additive value for predicting clinical out- come when baseline measures of hemodynamic severity and functional status are considered. In addition, recording hemodynamics with exercise is challenging, and simpler parameters are ade- quate in most patients.2 4,6 11 2. As reported in several prospective and retrospec- tive studies, the risk of exercise testing is low in asymptomatic patients with AS. However, exer- cise testing is avoided in symptomatic patients with AS because of a high risk of complications, including syncope, ventricular tachycardia, and death. In a prospective survey of 20 medical cen- ters in Sweden that included 50000 exercise tests done over an 18-month period, the complication rate was 18.4 per 10000 tests; morbidity rate, 5.2 per 10000 tests; and mortality rate, 0.4 per 10000 tests. Although the number of patients with AS was not reported, 12 of the 92 complica- tions occurred in patients with AS: 8 had a decline in blood pressure during exercise, 1 had asystole, and 3 had ventricular tachycardia.2,4,5,7 10,12 3.2.2. Medical Therapy Recommendations for Medical Therapy of AS Referenced studies that support the recommendations are summarized in Online Data Supplement 5. COR LOE Recommendations In patients at risk of developing AS (Stage A) and in patients with asymptomatic AS (Stages B and C), hypertension should be treated according to standard GDMT, started at a low dose, and gradually titrated upward as needed, with appropriate clinical In all patients with calcific AS, statin therapy is indicated for primary and secondary prevention of atherosclerosis on the basis of standard risk scores.4 6 In patients who have undergone TAVI, renin angiotensin system blocker therapy (ACE inhibitor or ARB) may be considered to reduce the long-term risk of all-cause mortality.7,8 Benefit A In patients with calcific AS (Stages B and C), statin therapy is not indicated for prevention of hemodynamic progression of AS.4 6 Synopsis Medical treatment of hypertension and hyperlipidemia according to GDMT is appropriate for patients with AS. ACE inhibitor or ARB treatment may reduce the mortal- ity rate in patients with AS who underwent TAVI. Recommendation-Specific Supportive Text 1. Hypertension is common in patients with AS, may be a risk factor for AS, and adds to the total pres- sure overload on the LV in combination with valve obstruction. Concern that antihypertensive medi- cations might result in a decrease in cardiac output has not been corroborated in studies of medical therapy, including 2 small RCTs, likely because AS does not result in fixed valve obstruction until late in the disease process. In 1616 patients CLINICAL STATEMENTS AND GUIDELINES with asymptomatic AS in the SEAS (Simvastatin Ezetimibe in Aortic Stenosis) study, hypertension (n=1340) was associated with a 56% higher rate of ischemic cardiovascular events and a 2-fold higher mortality rate (both P<0.01) than those seen in normotensive patients with AS, although no impact on progression of valve stenosis lead- ing to symptoms requiring AVR was seen. Medical therapy for hypertension follows standard guide- lines, starting at a low dose and gradually titrating upward as needed to achieve blood pressure con- trol. There are no studies addressing specific anti- hypertensive medications in patients with AS, but diuretics may reduce stroke volume, particularly if the LV chamber is small at baseline. In theory, ACE inhibitors may be advantageous because of the potential beneficial effects on LV fibrosis, in addi- tion to control of hypertension. Consideration should be given to a higher target blood pressure for patients with AS than is recommended for the general population, but this is an underexplored area, and further data are needed before a differ- ent target blood pressure can be recommended for patients with AS.1 3,9 13 2. Concurrent CAD is common in patients with AS, and all patients should be screened and treated for hypercholesterolemia, with GDMT used for primary and secondary prevention of CAD. In RCTs of statin therapy for mild to moderate AS, although aortic valve event rates were not reduced, the rate of ischemic events was reduced by about 20% in the statin therapy group even though these patients did not meet standard cri- teria for statin therapy.4 6,14,15 3. In patients undergoing TAVI, observational and registry data show that those who were treated with renin angiotensin system blocker therapy after the procedure had a lower 1-year mortality rate than those not treated with renin angio- tensin system blocker therapy, with a rela- tive risk reduction of about 20% to 50% and an absolute risk reduction between 2.4% and 5.0%. When stratified by LVEF, having a pre- scription for a renin angiotensin system inhibi- tor, versus no prescription, was associated with a lower 1-year mortality rate among patients with preserved LVEF but not among those with 4. Despite experimental models and retrospective clinical studies suggesting that lipid-lowering therapy with a statin might prevent disease pro- gression of calcific AS, 3 large well-designed RCTs failed to show a benefit, either in terms of changes in hemodynamic severity or in clinical outcomes, in patients with mild to moderate valve obstruc- tion. Thus, at the time of publication, there are no data to support the use of statins for prevention of progression of AS.7,8,16,17 3.2.3. Timing of Intervention Recommendations for Timing of Intervention of AS Referenced studies that support the recommendations are summarized in Online Data Supplements 4 and 6 to 10. COR LOE Recommendations In adults with severe high-gradient AS (Stage D1) and symptoms of exertional dyspnea, HF, angina, syncope, or presyncope by history or on exercise testing, AVR is indicated.1 7 In asymptomatic patients with severe AS and an LVEF <50% (Stage C2), AVR is In asymptomatic patients with severe AS (Stage C1) who are undergoing cardiac surgery for other indications, AVR is In symptomatic patients with low-flow, low- gradient severe AS with reduced LVEF (Stage In symptomatic patients with low-flow, low- gradient severe AS with normal LVEF (Stage D3), AVR is recommended if AS is the most likely cause of symptoms.25 27 In apparently asymptomatic patients with severe AS (Stage C1) and low surgical risk, AVR is reasonable when an exercise test demonstrates decreased exercise tolerance (normalized for age and sex) or a fall in systolic blood pressure of 10 mmHg from baseline to peak exercise.13,28 30 In asymptomatic patients with very severe AS (defined as an aortic velocity of 5 m/s) and low surgical risk, AVR is reasonable.15,31 35 In apparently asymptomatic patients with severe AS (Stage C1) and low surgical risk, AVR is reasonable when the serum B-type natriuretic peptide (BNP) level is >3 times normal.32,36 38 In asymptomatic patients with high-gradient severe AS (Stage C1) and low surgical risk, AVR is reasonable when serial testing shows an increase in aortic velocity 0.3 m/s per year.39,40 In asymptomatic patients with severe high- gradient AS (Stage C1) and a progressive decrease in LVEF on at least 3 serial imaging studies to <60%, AVR may be In patients with moderate AS (Stage B) who are undergoing cardiac surgery for other indications, AVR may be considered. Synopsis See the table of recommendations for a summary of recommendations from this section and Figure 2 for indications for AVR in patients with AS. These recom- mendations for timing of intervention for AS apply to both SAVR and TAVI. The integrative approach to as- sessing risk of SAVR or TAVI is discussed in Section 2.5. The specific type of intervention for AS is discussed in Section 3.2.4. CLINICAL STATEMENTS AND GUIDELINES Recommendation-Specific Supportive Text 1. In symptomatic patients with severe high-gradi- ent AS (Stage D1), ample evidence demonstrates the beneficial effects of AVR on survival, symp- toms, and LV systolic function.35,41 46 The most common initial symptom of AS is exertional dys- pnea or decreased exercise tolerance. Clinical vigilance is needed to recognize these early symptoms and proceed promptly to AVR. More severe classical symptoms of AS, including HF, syncope, or angina, can be avoided by appropri- ate treatment at the onset of even mild symp- toms. Outcomes after surgical or transcatheter AVR are excellent in patients who do not have a high procedural risk.41,43 45 Surgical series demon- strate improved symptoms after AVR, and most patients have an improvement in exercise toler- ance, as documented in studies with pre- and post-AVR exercise stress testing.41,43 46 Historical observation studies on outcomes in symptomatic patients with severe AS have been confirmed in RCTs comparing TAVI with palliative care in patients with a prohibitive surgical risk. The choice of surgical versus transcatheter AVR for patients with an indication for AVR is discussed in Section 3.2.4.1 3,5,6,12 16,35,42,47 55 2. In asymptomatic patients with severe AS and normal LV systolic function, the survival rate dur- ing the asymptomatic phase is similar to that of age-matched controls, with a low risk of sud- den death (<1% per year) when patients are fol- lowed prospectively and when patients promptly report symptom onset. However, in patients with a low LVEF and severe AS, survival is better in those who undergo AVR than in those treated medically. The depressed LVEF in many patients is caused by excessive afterload (afterload mis- match), and LV function improves after AVR in such patients. If LV dysfunction is not caused Figure 2. Timing of intervention for AS. Colors correspond to Table 2. Arrows show the decision pathways that result in a recommendation for AVR. Periodic monitoring is indicated for all patients in whom AVR is not yet indicated, including those with asymptomatic (Stage C) and symptomatic (Stage D) AS and those with low-gradient AS (Stage D2 or D3) who do not meet the criteria for intervention. See Section 3.2.4 for choice of valve type (mechanical versus bioprosthetic [TAVI or SAVR]) when AVR is indicated. AS indicates aortic stenosis; AVA, aortic valve area; AVAi, aortic valve area index; AVR, aortic valve replacement; BNP, B-type natriuretic peptide; BP, blood pressure; DSE, dobutamine stress echocardiography ETT, exercise treadmill test; LVEF, left ventricular ejection fraction; Pmean , mean systolic pressure gradient between LV and aorta; SAVR, surgical aortic valve replacement; SVI, stroke volume index; TAVI, transcatheter aortic valve implantation; TAVR, transcatheter aortic valve replace- ment; and Vmax , maximum velocity. CLINICAL STATEMENTS AND GUIDELINES by afterload mismatch, survival is still improved, likely because of the reduced afterload with AVR, but improvement in LV function and reso- lution of symptoms might not be complete after 3. Prospective clinical studies demonstrate that dis- ease progression occurs in nearly all patients with severe asymptomatic AS. Symptom onset within 2 to 5 years is likely when aortic velocity is 4.0 m/s or mean pressure gradient is 40 mmHg. The additive risk of AVR at the time of other cardiac surgery is less than the risk of reoperation within 4. Mean pressure gradient is a strong predic- tor of outcome after AVR, with better out- comes seen in patients with higher gradients. Outcomes are poor with severe low-gradient AS but are still better with AVR than with medi- cal therapy in those with a low LVEF, particu- larly when contractile reserve is present. The document Echocardiographic Assessment of Valve Stenosis: EAE/ASE Recommendations for Clinical Practice defines severe AS on dobuta- mine stress testing as a maximum velocity >4.0 m/s with a valve area 1.0 cm2 at any point dur- ing the test protocol, with a maximum dobu- tamine dose of 20 mcg/kg per minute.66 The recommendation for AVR in these patients is based on outcome data in several prospective nonrandomized studies. LVEF typically increases by 10 LVEF units and may return to normal if afterload mismatch was the cause of LV systolic dysfunction. If dobutamine stress testing indi- cates moderate, not severe AS, GDMT for HF can be continued without AVR. Patients without contractile reserve may also benefit from AVR, but decisions in these high-risk patients must be individualized because outcomes are poor with either surgical or medical therapy. The role of TAVI in these patients is currently under 5. A subset of patients with severe AS presents with symptoms and with a low velocity, low gradient, and low stroke volume index, despite a normal LVEF. Low-flow, low-gradient severe AS with preserved LVEF should be considered in patients with a severely calcified aortic valve, an aortic velocity <4.0 m/s (mean pressure gradient <40 mmHg), and a valve area 1.0 cm2 when stroke volume index is <35 mL/m2 . Typically, the LV is small, with thick walls, diastolic dysfunction, and a normal LVEF ( 50%). The first diagnostic step is to ensure that data were recorded and mea- sured correctly. If hypertension is present, blood pressure is controlled before reevaluation of AS severity. Next, valve area is indexed to body size because an apparent small valve area may be only moderate AS in a small patient; an aortic valve area index 0.6 cm2 suggests severe AS. Transaortic stroke volume is calculated by Doppler or 2D imaging. Measurement of a CT calcium score often is helpful. Evaluation for other potential causes of symptoms ensures that symptoms are most likely attributable to valve obstruction. Although the survival rate after TAVI is lower in patients with low-flow severe AS than in patients with normal-flow severe AS, AVR appears beneficial, with an increase in stroke volume and improved survival as compared with 6. Exercise testing may be helpful in clarifying symptom status in patients with severe AS. When symptoms are provoked by exercise test- ing, the patient is considered symptomatic and meets a COR 1 recommendation for AVR; symp- toms are symptoms, whether reported sponta- neously by the patient or provoked on exercise testing. The rate of symptom onset within 1 to 2 years is high (about 60% to 80%) in patients without overt symptoms who demonstrate 1) a fall of 10 mm Hg in systolic blood pressure from baseline to peak exercise or 2) a significant decrease in exercise tolerance as compared with age and sex normal standards. Management of patients with a lack of appropriate rise in BP with exercise is less clear. Decisions about elective AVR in these patients include consid- eration of surgical risk, patient preferences, and clinical factors, such as age and comorbid 7. In patients with very severe AS and an aortic velocity 5.0 m/s or mean pressure gradient 60 mmHg, the rate of symptom onset is approxi- mately 50% at 2 years. 