Nothing to Disclose Gabriel Gregoratos, MD, FACC, FAHA Questions - PDF document

12/16/16 Disclosure Asymptomatic Severe Aortic Stenosis: (When) Should One Intervene? Nothing to Disclose Gabriel Gregoratos, MD, FACC, FAHA Questions Paul Wood at the Nathanson Lecture, 1958 • Can one improve globally on the asymptomatic state? and if not “ Aortic stenosis is a simple • Can one improve quality of life and life mechanical fault which, if severe expectancy by intervening in asymptomatic enough, imposes a heavy burden patients? on the left ventricle and sooner or later overcomes it” 1

12/16/16 Natural History of Valvular AS Case 1 (1969)- US Army Hospital Munich (Ross & Braunwald, Circulation 1968) • 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 Case 2 (1977)- UCSD • 68 year-old retiring movie director • Although the incidence of Sudden Death in • Totally asymptomatic and active for his age asymptomatic severe AS is ~1 to 1.5%, consequences • Clinical and echo findings of severe AS can be devastating • Cardiac cath: 54 mmHg mean gradient, AVA 0.7 cm 2 , no • Subsequently at least one study reported a higher SD significant coronary artery disease incidence of 4 % and others have reported 1.5% and • Initially refused surgery, but later agreed 2% SD rate in patients with asymptomatic severe AS • 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

12/16/16 Natural History of Aortic Stenosis Lesson from Case # 2 (Ross & Braunwald, Circulation 1968) ? • 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 𝐵 = 𝜌𝑠 % gradually to their limitations and don’t recognize them; they downregulate their exercise level Valvular Heart Disease Stages of Valvular Aortic Stenosis and the Guidelines Stage Definition Valve Anatomy Valve Hemodynamic Symptoms Hemodynamics Consequences C - Asymptomatic severe AS C1 Asymptomatic ● Severe leaflet ● Aortic V max ³ 4 m/s ● LV diastolic ● None– • “A Guideline is only a guideline” or mean D P ≥40 severe AS calcification or dysfunction exercise congenital mm Hg ● Mild LV testing is • “A clinician who follows the recommendations stenosis with ● AVA typically is hypertrophy reasonable ≤1 cm 2 (or AVAi severely ● Normal LVEF to confirm of the guidelines 100% of the time, is not doing reduced leaflet £ 0.6 cm 2 /m 2 ) symptom opening ● Very severe AS is status his/her job properly as a physician”. an aortic V max ≥5 m/s, or mean D P ≥60 mm Hg (Nishimura and Carabello. JACC 2016;67:2289) C2 Asymptomatic ● Severe leaflet ● Aortic V max ≥4 m/s ● LVEF <50% ● None severe AS with calcification or or mean D P ≥40 LV congenital mm Hg dysfunction stenosis with ● AVA typically is ≤1 cm 2 (or AVAi severely reduced leaflet £ 0.6 cm 2 /m 2 ) opening 3

12/16/16 Class I Recommendations for TTE Aortic Stenosis: Timing of Intervention Follow-up of Patients with AS 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 I B C or D) when undergoing other cardiac surgery ACC/AHA VHD Guideline, JACC 2014 Aortic Stenosis: Timing of Intervention (cont.) Aortic Stenosis: Timing of Intervention (cont.) Recommendations COR LOE Recommendations COR LOE AVR is reasonable for asymptomatic patients AVR is reasonable in symptomatic patients who with very severe AS (stage C1, aortic velocity IIa B have low-flow/low-gradient severe AS (stage D3) ≥5 m/s) and low surgical risk*** who are normotensive and have an LVEF ≥50% if IIa C AVR is reasonable in asymptomatic patients clinical, hemodynamic, and anatomic data support (stage C1) with severe AS and decreased IIa B valve obstruction as the most likely cause of exercise tolerance or an exercise fall in BP symptoms AVR is reasonable in symptomatic patients with AVR is reasonable for patients with moderate AS low-flow/low-gradient severe AS with reduced (stage B) (aortic velocity 3.0–3.9 m/s) who are IIa C LVEF (stage D2) with a low-dose dobutamine undergoing other cardiac surgery IIa B stress study that shows an aortic velocity ³ 4 m/s AVR may be considered for asymptomatic (or mean pressure gradient ³ 40 mm Hg) with a patients with severe AS (stage C1) and rapid*** IIb C valve area £ 1.0 cm 2 at any dobutamine dose disease progression and low surgical risk *** OP mortality<1.5% ***Vmax ≥ 0.3 m/s per year 4

12/16/16 Issues with Intervention in Sources of Error in Defining Asymptomatic Severe AS AS Severity • Guideline recommendations based on observational non- • Underestimation of LVOT diameter randomized studies and expert opinion(Evidence level B or C) • Underestimation of mean Gradient by • Definition of “severe” AS is debated and changing misalignment of Doppler with flow direction • Mismatch between AVA and gradient is a common confounding problem due to measurement errors • Misinterpretation of AS severity by failure to • Grading AS severity by different methods can be inconsistent consider Flow which can affect Gradient • 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 Echo – Catheterization Discordance Is this Severe AS? From Nishimura and Carabello. JACC 2016;67:2289 • 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 Event-Free Survival in Asymptomatic AS Patients with initial Vpeak ≥ 2.5 m/sec. Events: Death or AVR 26% Months 0 12 24 36 48 60 Otto et al. Circulation 1997 Otto et al. Circulation 1997 Predictors of Outcome Two Patients with Severe AS (Otto et al. Circulation 1997) POSITIVE NEGATIVE • Aortic jet velocity, mean • Age, gender, cause of AS gradient, valve area • LVEF, LV mass • More rapid rate of annual • Pulmonary artery change in jet velocity(>0.3 pressure m/sec) and gradient • Diastolic dysfunction • Functional status at entry • Exercise duration • Blood pressure drop with exercise (±) 6

12/16/16 Outcomes of Severe Asymptomatic AS in Long-term Outcomes of 622 Asymptomatic 103 Elderly Patients (Vmax>4 m/s) Adults with Severe AS (Vpeak ≥ 4 m/s) “One may not gain much by waiting” Bonow R; JACC 2015 ↑ ↑ 82% 63% ↑ 25% 5 333 % % Zilberszac et al. JACC CV Imaging 2016 Pellikka et al. Circulation. 2005 Echo Predictors of Event-free Survival Hemodynamic Definition of Severe AS in1065 Patients with Severe AS ( Event: Composite of • AVA ≤ 1 cm 2 vs. ≤ 0.8 cm 2 ? AVR and Death ) • 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 2016 7

12/16/16 Low-Flow Low-Gradient AS L ow 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 Low- Flow 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, 2002 150 Asymptomatic Severe AS Patients Box-Plot of BNP Levels All with EF ≥ 55% and AVA ≤ 1cm 2 7% Normal Flow: SVi ≥ 35 ml/m 2 High Gradient: ≥ 30 mmHg 10% 31% 52% Lancelloti et al. JACC 2012 Lancelloti et al. JACC 2012 8

12/16/16 NT-pro-BNP Levels Alternative Definition of Severe AS According to Severity of 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 CV Mortality in Echo Predictors of All-cause Mortality in 1065 Patients with Severe AS 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 2016 9