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

12/16/16 1

Asymptomatic Severe Aortic Stenosis: (When) Should One Intervene?

Gabriel Gregoratos, MD, FACC, FAHA

Disclosure

Nothing to Disclose

• 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?

Questions

“Aortic stenosis is a simple

mechanical fault which, if severe enough, imposes a heavy burden

• n the left ventricle and sooner
• r later overcomes it”

Paul Wood at the Nathanson Lecture, 1958

12/16/16 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 cm2, 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.”

12/16/16 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)

?

𝐵 = 𝜌𝑠%

Valvular Heart Disease and the Guidelines

• “A Guideline is only a guideline”
• “A clinician who follows the recommendations
• f 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 Hemodynamic Consequences Symptoms C - Asymptomatic severe AS C1 Asymptomatic severe AS

• Severe leaflet

calcification or congenital stenosis with severely reduced leaflet

• pening
• Aortic Vmax ³4 m/s
• r mean DP ≥40

mm Hg

• AVA typically is

≤1 cm2 (or AVAi £0.6 cm2/m2)

• Very severe AS is

an aortic Vmax ≥5 m/s, or mean DP ≥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 dysfunction

• Severe leaflet

calcification or congenital stenosis with severely reduced leaflet

• pening
• Aortic Vmax ≥4 m/s
• r mean DP ≥40

mm Hg

• AVA typically is

≤1 cm2 (or AVAi £0.6 cm2/m2)

• LVEF <50%
• None

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Class I Recommendations for TTE Follow-up of Patients with AS

ACC/AHA VHD Guideline, JACC 2014

Aortic Stenosis: Timing of Intervention

Recommendations COR LOE AVR is recommended with severe high-gradient AS who have symptoms by history or on exercise testing (stage D1) I B AVR is recommended for asymptomatic patients with severe AS (stage C2) and LVEF <50% I B AVR is indicated for patients with severe AS (stage C or D) when undergoing other cardiac surgery I B

Aortic Stenosis: Timing of Intervention (cont.)

Recommendations COR LOE AVR is reasonable for asymptomatic patients with very severe AS (stage C1, aortic velocity ≥5 m/s) and low surgical risk*** IIa B AVR is reasonable in asymptomatic patients (stage C1) with severe AS and decreased exercise tolerance or an exercise fall in BP IIa B 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 cm2 at any dobutamine dose IIa B

*** OP mortality<1.5%

Aortic Stenosis: Timing of Intervention (cont.)

Recommendations COR LOE 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 IIa C AVR is reasonable for patients with moderate AS (stage B) (aortic velocity 3.0–3.9 m/s) who are undergoing other cardiac surgery IIa C AVR may be considered for asymptomatic patients with severe AS (stage C1) and rapid*** disease progression and low surgical risk IIb C

***Vmax≥0.3 m/s per year

12/16/16 5 Issues with Intervention in Asymptomatic Severe AS

• Guideline recommendations based on observational non-

randomized 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
• utcomes 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 cm2 and AVA index 0.6 cm2 /m2 ► YES, even though only the AVA index meets guideline definition of severe AS

12/16/16 6

Event-free Survival in 123 Asymptomatic AS Patients with initial Vpeak≥ 2.5 m/sec.

26%

Otto et al. Circulation 1997 Events: Death or AVR

Event-Free Survival in Asymptomatic AS

Months 0 12 24 36 48 60

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 (±)

NEGATIVE

• Age, gender, cause of AS
• LVEF, LV mass
• Pulmonary artery

pressure

• Diastolic dysfunction
• Exercise duration

Two Patients with Severe AS

12/16/16 7

Long-term Outcomes of 622 Asymptomatic Adults with Severe AS (Vpeak≥4 m/s)

Pellikka et al. Circulation. 2005

↑ ↑ ↑

82% 63%

333%

“One may not gain much by waiting” Bonow R; JACC 2015

Outcomes of Severe Asymptomatic AS in 103 Elderly Patients (Vmax>4 m/s)

Zilberszac et al. JACC CV Imaging 2016

25%5

%

Echo Predictors of Event-free Survival in1065 Patients with Severe AS

Capoulade R, et al. Heart 2016

(Event: Composite of

AVR and Death)

Hemodynamic Definition of Severe AS

• AVA ≤1 cm2 vs. ≤0.8 cm2 ?
• Mean Gradient ≥35 vs.≥40 vs. ≥50 mmHg ?
• Peak aortic jet velocity ≥3.5 vs. ≥4 vs. ≥5 m/sec?
• AVAi ≤0.6 cm2/m2

_______________________________________________________________

• What is the Flow (SVi) and why is it important?

12/16/16 8

• 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

Low Flow-Low Gradient AS Low-Flow Low-Gradient AS

Dobutamine→SV ↑ and Gradient ↑ >20% = Good inotropic Reserve Successful AVR and Reasonably Good Outcome Nishimura et al, Circulation 106:809, 2002

150 Asymptomatic Severe AS Patients All with EF≥55% and AVA≤1cm2

Lancelloti et al. JACC 2012 52% 7% 31% 10% High Gradient: ≥30 mmHg Normal Flow: SVi≥35 ml/m2

Box-Plot of BNP Levels

Lancelloti et al. JACC 2012

12/16/16 9

NT-pro-BNP Levels According to Severity of AS

Weber M et al. Am J Cardiol 2004;94:740

Alternative Definition of Severe AS

Severe AS is that level of left ventricular (LV)

• utflow 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

Echo Predictors of All-cause Mortality in 1065 Patients with Severe AS

Capoulade R, et al. Heart 2016

The most powerful echocardiographic predictors of mortality are low LVEF and low flow

Echo Predictors of CV Mortality in 1065 Patients with Severe AS

Capoulade R, et al. Heart 2016

12/16/16 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 cm2)

Carstensen HG Erop Heart J-CV Imaging 2016; 17:283

Synergistic Utility of BNP and LV Strain in Patients With Significant Aortic Stenosis

Goodman et al. J Am Heart Assoc. 2016;5:e002561

Valvulo-arterial impedance (Zva) Index of Global LV Load

• Calculated as:
• Zva = (SAP +Mean Gradient)/SVi)
• (SAP = systolic arterial pressure)
• (SVi = indexed stroke volume)

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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. 0.65 cm2)

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. 4.37 m/s)

*on multivariate analysis Zva was best independent predictor of mortality with best predictive value of 6.1 mmHg x ml/m2)

Banovic et al. J Heart Valve Disease 2015; 24:156

Late Gadolinium Enhancement by Cardiac MRI in a Patient with Severe AS

Barone-Rochette et al JACC 2014;64:144

Mid wall fibrosis

Correlation of Myocardial Fibrosis by LGE-CMR and Histologically

Azevedo CF et al. JACC 2010; 56:278

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 Dweck MR et al JACC 2011; 58:1271 No difference in EF between survivors and non- survivors (57% vs. 58%)

12/16/16 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;104:972–977

Adverse Events During Stress Testing in 5060 Patients with Severe CV Diseases (212 SAS)

Skalski J et al. Circulation 2012;126:2465

No AE in AS cohort

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

• r mean pressure gradient 40 mm Hg or higher

(stage C) IIa B 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

12/16/16 13

Exercise Stress Echocardiography for Risk Stratification of Asymptomatic Severe AS

Marechaux S et al. Europ Heart J 2010;31:1390

Outcomes of 338 Asymptomatic Patients with Severe AS (Retrospective)

PAI et al. Ann Thoracic Surg. 2006

AVA≤0.8 cm2

Outcomes of 197 Consecutive Patients with Very Severe Asymptomatic AS (Prospective)

Inclusion Criteria

• V max ≥4.5 m/sec.
• AVA ≤ 0.75 cm2
• Mean gradient ≥ 50 mmHg
• LVEF ≥ 50%

Exclusion Criteria

• Symptoms (angina, syncope,

exertional dyspnea)

• LVEF < 50%
• Age > 85 years

Kang et al. Circulation 2010

AVR Results : 197 Consecutive Patients with Very Severe Asymptomatic AS

Kang et al. Circulation 2010 V max 5.1 m/s V max 4.9 m/s

12/16/16 14

AVR Results : 197 Consecutive Patients with Very Severe Asymptomatic AS

V max 5.1 m/s V max 4.9 m/s Kang et al. Circulation 2010

All-cause Death: Patients with Severe AS

291-Early AVR vs. 291-Watchful Waiting (Retrospective Study)

Taniguchi T et al. JACC 2015;66:2827

Vmax>4m/s mPG>40 mmHg AVA<1cm2

HF Hospitalization: Patients with Severe AS 291-Early AVR vs. 291-Watchful Waiting (Retrospective Study)

Taniguchi T et al. JACC 2015;66:2827

Vmax>4m/s mPG>40 mmHg AVA<1cm2

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

12/16/16 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

12/16/16 16 Asymptomatic Severe Aortic Stenosis: (When) Should One Intervene? Supplemental Slides

Generaux et al. JACC 2016:67:2263