Dr Charles T IttyInterventional Cardiology Fellow

John Hunter HospitalNewcastle

Natural history ofAortic stenosis

Calcareous (calcific) aortic valve stenosis was first described by Mockeberg in 1904.

Monckeberg, J. G. (1904). Virchows Archiv fur athologische Anatomie und Physiology undfur Klinische Medizin, 176, 472.

Dry, T. J., and Willius F. A.: Am. Heart Journal, 17:138-157 (Feb.), 1939.

Dry, T. J., and Willius F. A. Am. Heart Journal, 17:138-157 (Feb.), 1939.

Causes of death (n=106):Congestive heart failure, 32 patients (3o.5%)Sudden death, 18 patients (17%)Infective endocarditis, 5 patients (4.7%)Acute coronary occlusion, 1 patient (0.9%)Non cardiac cause, 50 patients (47%).

Dry, T. J., and Willius F. A.: Am. Heart Journal, 17:138-157 (Feb.), 1939.

‘Majority of patients who died when the syndrome of congestive heart failure was present responded to therapy in a rather disappointing manner ...’

‘Symptoms are likely to remain in abeyance for many years, but with the onset of myocardial failure the outlook becomes serious’.

Dry, T. J., and Willius F. A.: Am. Heart Journal, 17:138-157 (Feb.), 1939.

Beginning of cardiac cath.

1947 - Zimmerman discovered the technique of left heart cardiac catheterization.

He was later awarded the Nobel Prize for combined cardiac catheterization. 

The evaluation of the natural history of aortic stenosis has been difficult, because the development of objective means for

assessment of its severity by left heart catheterization, and

the initial attempts at operative treatment,occurred almost simultaneously.

‘The natural course of aortic stenosis was assembledfrom clinical and postmortem studies largely

from before 1955, andfrom a few more recent analyses that are

supported by hemodynamic information’.

Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38(suppl 5):V61-67

Patients included in this analysis:Isolated valvular aortic stenosis of rheumatic

aetiology.Isolated calcific aortic stenosis with no history

of rheumatic fever. (many were considered to have congenitally bicuspid valve).

The review focussed primarily on the prognostic significance of three major symptomsangina pectoris,syncope andsymptoms of left ventricular failure.Ross J, Braunwald E. Aortic stenosis. Circulation 1968;

38(suppl 5):V61-67

Symptoms usually begin during the sixth decade of life following a long latent period.

This silent period is marked byProgressive stenosis, due to thickening and

calcificationAnd/or by progressive myocardial dysfunction.

Once symptoms develop, the average course is short, culminating in death at an average age of 63 years.

Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38(suppl 5):V61-67

The average durations of various symptoms were:Angina pectoris: 3 years,Syncope: 3 years,Dyspnea: 2 years andCongestive heart failure: 1.5 to 2 years.

Data from postmortem studies

Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38(suppl 5):V61-67

Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38(suppl 5):V61-67

Congestive heart failure: 50-60%.Infective endocarditis: 15-20%.Sudden death: 15-20%.

Causes of death

Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38(suppl 5):V61-67

Tended to occur in patients with symptoms.65-80% of patients had history of angina

pectoris, heart failure, or syncope.12-20% of patients had evidence of old or

recent myocardial infarction.Only 3-5% of deaths appear to occur suddenly

in patients without symptoms.

Sudden death

Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38(suppl 5):V61-67

Surgical replacement of the aortic valve with a ball-valve prosthesis or aortic valve homograft:Early mortality was approximately 10%.Total mortality had averaged 23%.

In more than 80% of the survivors, the clinical result achieved has been described as good or excellent.

Surgery for Aortic stenosis.

Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38(suppl 5):V61-67

Changing aetiology of AS

The Euro Heart Surveyon Valvular Heart Disease

Iung B et al. Eur Heart J. 2003 Jul;24(13):1231-43.

Aortic stenosis in the 21st century is the result of 2 main pathological processes*Congenital bicuspid aortic valves andAtherosclerotic/calcific aortic valves.

The present patient population is older.They have more associated coronary artery

disease.There has been improvements in the

treatment of heart failure and infective endocarditis.

What has changed?

* Alpert JS. Am J Med. 2010 Oct;123(10):875-6.

They are present in 1% of all infants born (US data)#.

It is estimated that only 1 in 50 of children have clinically significant valve disease by adolescence*.

In the Olmsted County series (n=212), 27% of adults with BAV at baseline required cardiovascular surgery at 20 years of follow-up0.

They can develop clinically important aortic stenosis during late middle life, usually between the 5th and 6th decades of life#.

Bicuspid Aortic valves

#Alpert JS. Am J Med. 2010 Oct;123(10):875-6.*Bonow RO et al. J Am Coll Cardiol 2006;48:e1–148. 0Samuel C et al. J. Am. Coll. Cardiol. 2010;55;2789-2800

Degenerative calcific aortic stenosis usually manifests in individuals older than 75 years and occurs most frequently in males.

Often, these elderly patients have a number of associated co-morbid conditions which increases the surgical risk.

Degenerative calcific aortic stenosis

Townsend CM, et al. Sabiston Textbook of Surgery. 18th ed. Saunders; 2008:1841-1844.

Improvements in Surgery

An estimated 46,397 aortic valve replacements (AVR) were performed.

In-hospital mortality occurred in4.3% of first-time isolated AVR and 6.4% overall.

US Data from a 1994 Nationwide Inpatient Sample

Astor BC et al. Ann Thorac Surg. 2000 Dec;70(6):1939-45.

STS U.S. cardiac surgery database, 1997Patients in NYHA classes I or II had an

operative mortality of <2%NYHA III 3·7% andNYHA IV 7·0%

STS Database

European Heart Journal (2002) 23, 1417–1421

Can we generalize the results of the earlier studies to the current patient population ?

Retrospective study of252 operated and47 unoperated patients (who refused surgery)with isolated aortic valve disease.

AVR was recommended to all patients based on clinical and hemodynamic data.

Circulation 1982; 66: 1105–10.

Circulation 1982; 66: 1105–10.

Schwarz F et al. The effect of aortic valve replacement on survival. Circulation 1982; 66: 1105–10.

362 patients with severe aortic stenosis who were screened and did not meet the inclusion/exclusion criteria for TAVI trial.Group 1 (medical): 274 (75.7%), (64.6% had

BAV).Group 2 (surgical): 88 (24.3%).

Circulation. 2010;122[suppl 1]:S37–S42.

Circulation. 2010;122[suppl 1]:S37–S42.

Circulation. 2010;122[suppl 1]:S37–S42.

Medical/BAV group: Death37.2% by 1

year53.4% by 2

years.

Circulation. 2010;122[suppl 1]:S37–S42.

Medical arm of PARTNER trial

Severe aortic stenosisAortic-valve area <0.8 cm2Mean aortic-valve gradient of 40 mm Hg or

more orPeak aortic-jet velocity of 4.0 m/s or more.

All patients had NYHA class II, III or IV symptoms.

Leon MB et al. (PARTNER Trial). NEJM. 363(17):1597-607, 2010 Oct 21.

Asymptomatic severe AS

Standard medical therapy (including BAV done in 83.8% patients) did not alter the natural history of severe aortic stenosis.

At the end of 1 year:Rate of death from any cause was 50.7% andRate of death from cardiovascular causes was

44.6%.

Leon MB et al. (PARTNER Trial). NEJM. 363(17):1597-607, 2010 Oct 21.

‘One of the clearest decisions for a doctor is to recommend valve replacement for individuals with severe symptomatic aortic stenosis’.

‘Such patients have a dire outlook, with three-quarters dying within 3 years of symptom onset’.

‘Aortic valve replacement can be withheld in such patients only when compelling contraindications exist’.

Severe symptomatic aortic stenosis

Aortic stenosis. Blase A Carabello, Walter J Paulus. Lancet 2009; 373: 956–66

Asypmtomatic AS

Many patients with limited or no symptoms yet hemodynamically significant aortic stenosis are being identified with the routine use of echo and cardiac cath.

The dilemma is how best to treat these patients.

180 patients with valvular AS followed up for 25 years.

They reported that sudden death:occurred "rarely" in totally asymptomatic

patients andwas often preceded by the development of

symptoms.

Contratto and Levine (1937)

Contratto AW eta al. Ann Intern Med 1937; 10:1636-53

Sudden death tended to occur in patients with symptoms.

Only 3 to 5% of the sudden deaths in acquired AS appear to occur in patients without symptoms.

It was proposed that patients with acquired valvular AS have surgery deferred until the onset of symptoms.

Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38(suppl 5):V61-67

Retrospective review of 73 patients with aortic stenosis.

17 asymptomatic or mildly symptomatic patients with severe AS or combined AS+AR.

None of the patients died or required valve surgery during the first 2 years.

At 5 years, 75% were event free (alive and not had surgery) and 94% survived.

Turina J et al (1987).

Turina J et al. Eur Heart J 1987; 8:471-83

They concluded that asymptomatic or minimally symptomatic patients with severe AS are at low risk of death and that surgical treatment can be postponed until "marked symptoms" appear.

Turina J et al. Eur Heart J 1987; 8:471-83

51 asymptomatic patients with severe AS.Followed up for a mean of 17 months.21 (41%) patients became symptomatic.Only two died of cardiac causes and both had

become symptomatic for at least 3 months prior.

The conclusion was, that patients be followed up until symptoms develop.

Kelly TA et al.

Kelly TA et al. Am J Cardiol 1988; 61:123-30

113 asymptomatic patients with significant AS.

Mean follow-up was 20 months.Three deaths:

2 sudden deaths1 congestive heart failure.

In each case, the development of symptoms preceded death by at least 3 months.

Conclusion was that asymptomatic AS patients be followed up closely until symptoms develop.

Pellikka P et al.

Pellikka P etal. J Am Coll Cardiol 1990; 15:1012-17

Asymptomatic patients are at low risk for complications or mortality.

Risk of sudden death is <1% per year.Surgical therapy should be considered as

soon as the patient develops symptoms.

Steven J et al. Chest 1998;113;1109-1114

Undertaking AVR in all asymptomatic patients would only benefit the <1% who would die suddenly before symptoms develop, while exposing all to the risks of surgery and prosthetic valve related complications.

Therefore, the thrust should be to define a high-risk group of asymptomatic patients in whom risk of no intervention is higher than that of AVR.

Aortic stenosis. Blase A Carabello, Walter J Paulus. Lancet 2009; 373: 956–66

Risk stratification might incorporateJet velocity,Progression of valvular narrowing,Response to exercise testing,Co-morbidity,Abnormally raised biomarkers,Presence of ventricular dysfunction,Degree of valvular calcification etc.

Aortic stenosis. Blase A Carabello, Walter J Paulus. Lancet 2009; 373: 956–66

128 consecutive patients with asymptomatic, severe aortic stenosis.

Followed up for a mean of 22±18 months.End point: Death (8 patients) or valve

replacement necessitated by the development of symptoms (59 patients).

N Engl J Med 2000; 343:611-7.

N Engl J Med 2000; 343:611-7.

Event-free survival was67±5% at one year,56±5% at 2 years and33±5% at 4 years.

Five of the six deaths from cardiac disease were preceded by symptoms.

One patient had sudden death while still asymptomatic.

N Engl J Med 2000; 343:611-7.

N Engl J Med 2000; 343:611-7.

The rate of progression of aortic-jet velocity was significantly higher in patients who had cardiac events. (0.45±0.38 vs. 0.14±0.18 m per second per year, P<0.001)

N Engl J Med 2000; 343:611-7.

In asymptomatic patients with aortic stenosis, it appears to be relatively safe to delay surgery until symptoms develop.

The presence of moderate or severe valvular calcification, together with a rapid increase in aortic-jet velocity, identifies patients with a very poor prognosis. These patients should be considered for early valve replacement.

N Engl J Med 2000; 343:611-7.

622 patients with asymptomatic AS with mean follow up of 5.4±4.0 years.

Peak systolic velocity ≥ 4 m/s.

Circulation. 2005;111:3290-3295.

Predictors of symptom developmentAV areaLVH.

Circulation. 2005;111:3290-3295.

Predictors of all-cause mortality.AgeCRFInactivityAV velocity

Circulation. 2005;111:3290-3295.

Most patients with asymptomatic, hemodynamically significant AS will develop symptoms within 5 years.

Sudden death without preceding symptoms occurred in 11 (4.1%) i.e. ≈1%/y.

Patients with peak velocity ≥4.5 m/s had a higher likelihood of developing symptoms (relative risk, 1.34) or having surgery or cardiac death (relative risk, 1.48).

Circulation. 2005;111:3290-3295.

107 patients with asymptomatic aortic stenosis followed up for 24 months.

Predefined end points:Death orAVR if symptoms or positive EST.

Circulation. 2009;120:69-75.

Circulation. 2009;120:69-75.

Score=[peak velocity (m/s)x2]+(natural logarithm of B-type natriuretic peptidex1.5)+1.5 (if female sex).

Event-free survival after 20 months was 80% for patients within the first score quartile compared with only 7% for the fourth quartile.

Circulation. 2009;120:69-75.

116 consecutive asymptomatic patients with median follow up of 41 months.

Very severe isolated aortic stenosis defined by a peak aortic jet velocity (AV-Vel)≥5.0 m/s.

End points: Cardiac death or indication for aortic valve replacement according to the accepted guidelines.

Circulation. 2010;121:151-156.

96 eventsAVR in 90 patients and cardiac deaths in 6 patients.

Sudden death without symptoms (n=1).Congestive heart failure (n=4)Myocardial infarction (n=1).

Circulation. 2010;121:151-156.

Circulation. 2010;121:151-156.

Circulation. 2010;121:151-156.

Patients with asymptomatic very severe aortic stenosis have a poor prognosis with a high event rate and a risk of rapid functional deterioration.

Early elective valve replacement surgery should therefore be considered in these patients.

Circulation. 2010;121:151-156.

Stenosis progression in aortic stenosis

The peak gradient changed by +12 mm Hg/yr (-10 to +34 mm Hg) and the

mean gradient changed by +8 mm Hg/yr (-7 to +23 mm Hg).

Mean reduction in aortic valve area of -0.1 cm2/yr (0.0 to -0.5 cm2).

Otto et al

J Am Coll Cardiol 1989; 13:545-50

Mean interval of 25 months,Peak gradient increased to 44±16 mm Hg.Average increase of 4.8 mm Hg/yr.

Roger et al.

Am Heart J 1990; 2:331-38

Stenosis progression in AS.

Steven J et al. Chest 1998;113;1109-1114

Overall, on average, the aortic valve area decreases by approximately 0.1 cm2/yr and the peak instantaneous gradient increases by 10 mm Hg/yr.

However, in any individual patient, this is highly variable.

Steven J et al. Chest 1998;113;1109-1114

There can be identified two distinct types of patients:those whose conditions progress slowly andothers whose conditions progress rapidly.

There are no reliable clinical predictors to help us identify into which subgroup an individual patient will fall.

Rapid Vs Slow progress.

Steven J et al. Chest 1998;113;1109-1114

Current guidelines

J. Am. Coll. Cardiol. 2008;52;e1-e142

J. Am. Coll. Cardiol. 2008;52;e1-e142

J. Am. Coll. Cardiol. 2008;52;e1-e142

J. Am. Coll. Cardiol. 2008;52;e1-e142

Currently available data suggest that careful weighing of risk and benefit does not justify the general recommendation of early elective surgery in asymptomatic patients with severe aortic stenosis.

Conclusions