Nothing to Disclose. Questions. Disclosure Asymptomatic Severe Aortic Stenosis: (When) Should One Intervene? Paul Wood at the Nathanson Lecture, 1958

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1 Disclosure Asymptomatic Severe Aortic Stenosis: (When) Should One Intervene? Nothing to Disclose Gabriel Gregoratos, MD, FACC, FAHA Questions Can one improve globally on the asymptomatic state? and if not Can one improve quality of life and life expectancy by intervening in asymptomatic patients? Paul Wood at the Nathanson Lecture, 1958 Aortic stenosis is a simple mechanical fault which, if severe enough, imposes a heavy burden on the left ventricle and sooner or later overcomes it 1

2 Natural History of Valvular AS (Ross & Braunwald, Circulation 1968) Case 1 (1969)- US Army Hospital Munich 36 year old Army orthopedist/colleague/friend Referred because of abnormal separation physical examination Avid skier; denied all symptoms Harsh, late peaking, grade iv/vi systolic M. preceded by an ejection sound. ECG: LVH by voltage Refused further workup, signed waiver, discharged Died suddenly while skiing in Aspen 8 months later Lesson from Case # 1 Although the incidence of Sudden Death in asymptomatic severe AS is ~1 to 1.5%, consequences can be devastating Subsequently at least one study reported a higher SD incidence of 4 % and others have reported 1.5% and 2% SD rate in patients with asymptomatic severe AS Case 2 (1977)- UCSD 68 year-old retiring movie director Totally asymptomatic and active for his age Clinical and echo findings of severe AS Cardiac cath: 54 mmhg mean gradient, AVA 0.7 cm 2, no significant coronary artery disease Initially refused surgery, but later agreed Underwent successful AVR In clinic 6 weeks later: Doctor, I am a new man; I had no idea how limited I was before surgery. 2

3 Lesson from Case # 2 Confirmed my notion that self assessment of symptoms and exercise capacity by patients with valvular disease is notoriously unreliable because Patients with valvular disease frequently adapt gradually to their limitations and don t recognize them; they downregulate their exercise level Natural History of Aortic Stenosis (Ross & Braunwald, Circulation 1968)? A = πr % Valvular Heart Disease and the Guidelines A Guideline is only a guideline A clinician who follows the recommendations of the guidelines 100% of the time, is not doing his/her job properly as a physician. (Nishimura and Carabello. JACC 2016;67:2289) Stages of Valvular Aortic Stenosis Stage Definition Valve Anatomy Valve Hemodynamics C - Asymptomatic severe AS C1 Asymptomatic severe AS C2 Asymptomatic severe AS with LV dysfunction Severe leaflet calcification or congenital stenosis with severely reduced leaflet opening Severe leaflet calcification or congenital stenosis with severely reduced leaflet opening Aortic V max ³4 m/s or mean DP 40 mm Hg AVA typically is 1 cm 2 (or AVAi 0.6 cm 2 /m 2 ) Very severe AS is an aortic V max 5 m/s, or mean DP 60 mm Hg Aortic V max 4 m/s or mean DP 40 mm Hg AVA typically is 1 cm 2 (or AVAi 0.6 cm 2 /m 2 ) Hemodynamic Consequences LV diastolic dysfunction Mild LV hypertrophy Normal LVEF Symptoms None exercise testing is reasonable to confirm symptom status LVEF <50% None 3

Class I Recommendations for TTE Follow-up of Patients with AS Aortic Stenosis: Timing of Intervention Recommendations COR LOE AVR is recommended with severe high-gradient AS who have symptoms by

undergoing other cardiac surgery I B ACC/AHA VHD Guideline, JACC 2014 Aortic Stenosis: Timing of Intervention (cont.) Aortic Stenosis: Timing of Intervention (cont.

4 Class I Recommendations for TTE Follow-up of Patients with AS Aortic Stenosis: Timing of Intervention Recommendations COR LOE AVR is recommended with severe high-gradient AS who have symptoms by history or on exercise I B testing (stage D1) AVR is recommended for asymptomatic patients with severe AS (stage C2) and LVEF I B <50% AVR is indicated for patients with severe AS (stage C or D) when undergoing other cardiac surgery I B ACC/AHA VHD Guideline, JACC 2014 Aortic Stenosis: Timing of Intervention (cont.) Aortic Stenosis: Timing of Intervention (cont.) Recommendations COR LOE AVR is reasonable for asymptomatic patients with very severe AS (stage C1, aortic velocity IIa B 5 m/s) and low surgical risk*** AVR is reasonable in asymptomatic patients (stage C1) with severe AS and decreased IIa B exercise tolerance or an exercise fall in BP AVR is reasonable in symptomatic patients with low-flow/low-gradient severe AS with reduced LVEF (stage D2) with a low-dose dobutamine stress study that shows an aortic velocity ³4 m/s (or mean pressure gradient ³40 mm Hg) with a valve area 1.0 cm 2 at any dobutamine dose IIa B Recommendations AVR is reasonable in symptomatic patients who have low-flow/low-gradient severe AS (stage D3) who are normotensive and have an LVEF 50% if clinical, hemodynamic, and anatomic data support valve obstruction as the most likely cause of symptoms AVR is reasonable for patients with moderate AS (stage B) (aortic velocity m/s) who are undergoing other cardiac surgery AVR may be considered for asymptomatic patients with severe AS (stage C1) and rapid*** disease progression and low surgical risk COR LOE IIa C IIa C IIb C *** OP mortality<1.5% ***Vmax 0.3 m/s per year 4

Issues with Intervention in Asymptomatic Severe AS Guideline recommendations based on observational nonrandomized studies and expert opinion(evidence level B or C)

different methods can be inconsistent LVEF may not the best or most sensitive predictor of outcomes because subclinical myocardial dysfunction occurs before EF

heterogeneity Sources of Error in Defining AS Severity Underestimation of LVOT diameter Underestimation of mean Gradient by misalignment of Doppler with flow

5 Issues with Intervention in Asymptomatic Severe AS Guideline recommendations based on observational nonrandomized studies and expert opinion(evidence level B or C) Definition of severe AS is debated and changing Mismatch between AVA and gradient is a common confounding problem due to measurement errors Grading AS severity by different methods can be inconsistent LVEF may not the best or most sensitive predictor of outcomes because subclinical myocardial dysfunction occurs before EF declines Optimal timing of intervention not clearly established Results of intervention in asymptomatic severe AS based on non-randomized studies with much heterogeneity Sources of Error in Defining AS Severity Underestimation of LVOT diameter Underestimation of mean Gradient by misalignment of Doppler with flow direction Misinterpretation of AS severity by failure to consider Flow which can affect Gradient Echo Catheterization Discordance From Nishimura and Carabello. JACC 2016;67:2289 Is this Severe AS? 63 year old man; has noticed decreasing exercise capacity from 2 flights to one Exam: Delayed carotid upstroke, late peaking SEM ECG: LVH with ST changes Echo: Vmax 3.6 m/s, Mean gradient 30 mmhg, AVA 1.1 cm 2 and AVA index 0.6 cm 2 /m 2 YES, even though only the AVA index meets guideline definition of severe AS 5

12/16/16 Event-free Survival in 123 Asymptomatic AS Patients with initial Vpeak 2.5 m/sec. Event-Free Survival in Asymptomatic AS Events: Death or AVR 26% Months Otto et al.

6 12/16/16 Event-free Survival in 123 Asymptomatic AS Patients with initial Vpeak 2.5 m/sec. Event-Free Survival in Asymptomatic AS Events: Death or AVR 26% Months Otto et al. Circulation 1997 Predictors of Outcome (Otto et al. Circulation 1997) POSITIVE Aortic jet velocity, mean gradient, valve area More rapid rate of annual change in jet velocity(>0.3 m/sec) and gradient Functional status at entry Blood pressure drop with exercise (±) Otto et al. Circulation 1997 Two Patients with Severe AS NEGATIVE Age, gender, cause of AS LVEF, LV mass Pulmonary artery pressure Diastolic dysfunction Exercise duration 6

7 Long-term Outcomes of 622 Asymptomatic Adults with Severe AS (Vpeak 4 m/s) 82% 63% One may not gain much by waiting Bonow R; JACC % Outcomes of Severe Asymptomatic AS in 103 Elderly Patients (Vmax>4 m/s) 25%5 % Pellikka et al. Circulation Zilberszac et al. JACC CV Imaging 2016 Echo Predictors of Event-free Survival in1065 Patients with Severe AS (Event: Composite of AVR and Death) Hemodynamic Definition of Severe AS AVA 1 cm 2 vs. 0.8 cm 2? Mean Gradient 35 vs. 40 vs. 50 mmhg? Peak aortic jet velocity 3.5 vs. 4 vs. 5 m/sec? AVAi 0.6 cm 2 /m 2 What is the Flow (SVi) and why is it important? Capoulade R, et al. Heart

12/16/16 Low Flow-Low Gradient AS Low-Flow Low-Gradient AS Dobutamine SV and Gradient >20% = Good inotropic Reserve Successful AVR and Reasonably Good Outcome Subset of patients with depressed LVEF,

8 12/16/16 Low Flow-Low Gradient AS Low-Flow Low-Gradient AS Dobutamine SV and Gradient >20% = Good inotropic Reserve Successful AVR and Reasonably Good Outcome Subset of patients with depressed LVEF, either due to longstanding severe AS or due to other causes such as ischemic cardiomyopathy, in whom the calculated AVA, MPG, and peak velocity are all low Second subset patients with normal EF and LowFlow due either to severely hypertrophied LV with small end-diastolic volume or due to subclinical myocardial damage at the sarcomere level Nishimura et al, Circulation 106:809, Asymptomatic Severe AS Patients All with EF 55% and AVA 1cm2 Normal Flow: SVi 35 ml/m2 High Gradient: 30 mmhg Box-Plot of BNP Levels 7% 10% 31% 52% Lancelloti et al. JACC 2012 Lancelloti et al. JACC

9 NT-pro-BNP Levels According to Severity of AS Alternative Definition of Severe AS Severe AS is that level of left ventricular (LV) outflow obstruction that causes 1) more than mild hypertrophy, 2)abnormal coronary blood flow, and 3) diastolic and systolic LV dysfunction that act in concert to cause symptoms, LV damage, and cardiac death. Carabello, JACC CV Imaging 2016 Weber M et al. Am J Cardiol 2004;94:740 Echo Predictors of All-cause Mortality in 1065 Patients with Severe AS Echo Predictors of CV Mortality in 1065 Patients with Severe AS The most powerful echocardiographic predictors of mortality are low LVEF and low flow Capoulade R, et al. Heart 2016 Capoulade R, et al. Heart

10 LV Performance in Severe AS Is the LVEF the most sensitive indicator? Probably NO Is LVEF 50% really normal? A cutoff of 50% is well-under 2 Std. Deviations of EF in healthy populations Is there subclinical myocardial dysfunction in severe AS and does it predict outcomes? Qualified YES (in ~50%) How do you detect subclinical myocardial dysfunction? *Exercise stress testing *Biomarkers (BNP and NT-proBNP) *Newer indices of LV performance other than EF: Global or Basal longitudinal LV strain; Valvulo-Arterial impedance *Focal myocardial fibrosis detected by LGE-CMR Outcomes in 104 Moderate-Severe Asymptomatic AS (AVA<1.5 cm 2 ) Carstensen HG Erop Heart J-CV Imaging 2016; 17:283 Synergistic Utility of BNP and LV Strain in Patients With Significant Aortic Stenosis Valvulo-arterial impedance (Zva) Index of Global LV Load Calculated as: Zva = (SAP +Mean Gradient)/SVi) (SAP = systolic arterial pressure) (SVi = indexed stroke volume) Goodman et al. J Am Heart Assoc. 2016;5:e

Mortality Predictors in 128 Patients with Asymptomatic Severe AS (3 yr. follow-up) POSITIVE (survivors vs. non-survivors) Lower Zva (4.86 vs. 7.81)* Lower NT-proBNP (377 vs. 1709) Higher AVA (0.86 vs. 0.

11 Mortality Predictors in 128 Patients with Asymptomatic Severe AS (3 yr. follow-up) POSITIVE (survivors vs. non-survivors) Lower Zva (4.86 vs. 7.81)* Lower NT-proBNP (377 vs. 1709) Higher AVA (0.86 vs cm 2 ) NEGATIVE (survivors vs. non-survivors) LV Ejection Fraction (72% vs. 70%) Mean Gradient (42 vs. 45 mmhg) Age (66 vs. 69) Vmax (4.2 vs m/s) *on multivariate analysis Zva was best independent predictor of mortality with best predictive value of 6.1 mmhg x ml/m 2 ) Banovic et al. J Heart Valve Disease 2015; 24:156 Late Gadolinium Enhancement by Cardiac MRI in a Patient with Severe AS Mid wall fibrosis Barone-Rochette et al JACC 2014;64:144 Correlation of Myocardial Fibrosis by LGE-CMR and Histologically Midwall Fibrosis: Independent Predictor of Mortality in 143 Patients With Aortic Stenosis Survival Estimates for CV Mortality in 143 Patients With Moderate or Severe Aortic Stenosis No difference in EF between survivors and nonsurvivors (57% vs. 58%) Azevedo CF et al. JACC 2010; 56:278 Dweck MR et al JACC 2011; 58:

12 Stress Testing in Asymptomatic Severe AS Bruce protocol (modified) /Physician in attendance Approx. 50% of pts with ASAS have abnormal stress test Indicators of poor long-term outcomes: Failure to achieve > 80% of MPHR Development of symptoms (dyspnea, chest pain, near syncope, reduced exercise capacity) Complex ventricular arrhythmia? Failure to increase SBP 20 mmhg (Guideline: Fall of BP) ST depression (down sloping/horizontal) 2 mm Exercise-induced symptoms in patients age < 70 years are predictive of Sudden Death (5% in one year in one study) Negative stress test predicts reduced risk>>>>>>> Billen E. et al. Journal of Heart Valve Disease 2014;23:524 Pooled Estimate of Outcomes in 491 Patients with Severe Asymptomatic AS and Negative Stress Testing Risk for All Cardiac Events Sudden Death Risk Rafique AM et al. Am J Cardiol 2009;104: Adverse Events During Stress Testing in 5060 Patients with Severe CV Diseases (212 SAS) No AE in AS cohort Skalski J et al. Circulation 2012;126:2465 Aortic Stenosis: Diagnosis and Follow-Up Recommendations COR LOE Exercise testing is reasonable to assess physiological changes with exercise and to confirm the absence of symptoms in asymptomatic patients with a calcified aortic valve and an aortic velocity 4.0 m per second or greater or mean pressure gradient 40 mm Hg or higher IIa B (stage C) Exercise testing should not be performed in symptomatic patients with AS when the aortic velocity is 4.0 m per second or greater or mean pressure gradient is 40 mm Hg or higher (stage D) III: Harm B 12

13 Exercise Stress Echocardiography for Risk Stratification of Asymptomatic Severe AS Outcomes of 338 Asymptomatic Patients with Severe AS (Retrospective) AVA 0.8 cm 2 Marechaux S et al. Europ Heart J 2010;31:1390 PAI et al. Ann Thoracic Surg Outcomes of 197 Consecutive Patients with Very Severe Asymptomatic AS (Prospective) AVR Results : 197 Consecutive Patients with Very Severe Asymptomatic AS Inclusion Criteria V max 4.5 m/sec. AVA 0.75 cm 2 Mean gradient 50 mmhg LVEF 50% Exclusion Criteria Symptoms (angina, syncope, exertional dyspnea) LVEF < 50% Age > 85 years V max 4.9 m/s V max 5.1 m/s Kang et al. Circulation 2010 Kang et al. Circulation

AVR Results : 197 Consecutive Patients with Very Severe Asymptomatic AS All-cause Death: Patients with Severe AS 291-Early AVR vs. 291-Watchful Waiting (Retrospective Study) V max 4.9 m/s V max 5.

14 AVR Results : 197 Consecutive Patients with Very Severe Asymptomatic AS All-cause Death: Patients with Severe AS 291-Early AVR vs. 291-Watchful Waiting (Retrospective Study) V max 4.9 m/s V max 5.1 m/s Vmax>4m/s mpg>40 mmhg AVA<1cm 2 Kang et al. Circulation 2010 Taniguchi T et al. JACC 2015;66:2827 HF Hospitalization: Patients with Severe AS 291-Early AVR vs. 291-Watchful Waiting (Retrospective Study) Vmax>4m/s mpg>40 mmhg AVA<1cm 2 AVR Results AVR after symptom development (n =247) was associated with higher 30-day operative mortality than AVR while asymptomatic (n=432) 3.7% vs. 1.2%, p=0.03 Taniguchi T et al. JACC 2015;66:2827 Taniguchi T et al. JACC 2015;66:

15 Pooled Estimates of SAVR Risk in 2486 pts with Severe Asymptomatic AS*- UNADJUSTED ADJUSTED Generaux et al. 2016; 67:2263 When considering Intervention in Asymptomatic Severe AS (1): Make sure measurements are correct and consistent Use current guideline recommendations, BUT... Don t wait for EF to fall to 50% Don t rely on self assessment of symptoms Use serial Exercise Stress Testing in conjunction with serial TTE to assess LV function and confirm absence of symptoms Exercise echo., BNP, CMR with LGE, and newer indices of LV function can help deciding when to intervene When considering Intervention in Asymptomatic Severe AS (2): Individualize decisions; consider patient s age and comorbidities and institutional/surgical issues Surgical AVR for asymptomatic severe AS in selected patients presupposes isolated AVR 30 day surgical mortality NO higher than 1-3 % Valve Center of Excellence Increasing applicability of TAVR may well alter criteria for intervention Thank You 15

16 Asymptomatic Severe Aortic Stenosis: (When) Should One Intervene? Supplemental Slides Generaux et al. JACC 2016:67:

Natural History and Echo Evaluation of Aortic Stenosis

Natural History and Echo Evaluation of Aortic Stenosis Prof. Patrizio LANCELLOTTI, MD, PhD Heart Valve Clinic, University of Liège, CHU Sart Tilman, Liège, BELGIUM AORTIC STENOSIS First valvular disease