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Three Part Question

In [Patients with severe aortic stenosis, poor left ventricular function and no reversibility ] is an [Aortic Valve Replacement superior to medical therapy] to improve [Survival or symptoms]

Clinical Scenario

You have been asked to evaluate a previously very fit 65 year old ex-mountaineer for aortic valve replacement(AVR). He first presented to the cardiologists in pulmonary oedema 2 weeks ago although he tells you that he has been getting gradually worse for 3 years. The transthoracic echo revealed an effective orifice area (EOA) of his aortic valve of 0.7cm2, left ventricular ejection fraction of 30%, and mean transaortic pressure difference of 25mmHg. The cardiologists performed a dobutamine stress echocardiography(DSE) that revealed a minimal rise in the systolic velocity integral (15%) and no increase in the EOA. The cardiologists feel that he is beyond the point at which an AVR would help him, but would value your opinion.

Search Strategy

Medline 1950–Nov 2007
[exp Aortic Valve Stenosis/ OR aortic stenosis.mp] AND [exp Ventricular Dysfunction, Left/ OR left ventricular dysfunction.mp OR exp Dobutamine OR Dobutamine stress.mp OR exp Heart Failure, Congestive/] AND [Thoracic Surgery.mp OR exp Thoracic Surgery/ OR AVR.mp OR valve replacement.mp ]

Search Outcome

A total of 251 papers were found. In addition all major guidelines were included and their reference lists searched. 14 papers were deemed to represent the best evidence on the topic and are summarized in the table

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Monin et al, 2003, USA	6 center study with prospective enrolment of 136 patients with aortic stenosis-median aortic valve area of 0.7cm2 , median transaortic gradient of 29mmHg and median cardiac index of 2.11L/min/m2. Patients divided into 2 groups based on DSE-group I (n=92) with contractile reserve- and group II(n=44) with no contractile reserve. 70% of patients in both groups had AVR -64 of 92 in group I and 31 of 44 in group II.	Cohort study (Level 2b)	Peri-operative mortality	Group I-5%-3 of 64 patients. Group II-32%-10 of 31 patients.	Number of patients in the group with no contractile reserve who underwent AVR still small though larger than in previous studies. Observational study-patients not randomized.
			Long term survival	Group I-Estimated 3 year survival of 79% after AVR, and 20% without AVR. Group II-around 35% after AVR , and 10% without AVR
			Post operative functional improvement	Group I- in 84% -54 of 64 patients. Group II- in 45%-14 of 31 patients.
Monin et al, 2001, France-Belgium	Low-dose DSE in 45 patients with median age 75, LVEF 29%, aortic valve area 0.7cm2 and mean transaortic gradient 26mmHg. Patients divided into 2 groups-group I with LV contractile reserve on DSE(n=32) and group II with no LV contractile reserve on DSE(n=13). AVR performed in 24 patients in group I and 6 in group II.	Cohort study (Level 2b)	Peri-operative mortality	Group I- 8% (2 of 24 patients) Group II- 50% (3 of 6 patients) (p=0.014).	Very small number of patients –only 6 patients in the group with no contractile reserve that underwent AVR. Observational study.
			Long term survival	Group I- 88%(21 of 24 patients) in those who had AVR. Group II- 1 of the 3 survivors died at 3 months. No data available about the outcome of the remaining 2 patients.
			Post operative functional improvement	Group I- Marked improvement in functional class - 17 patients initially in NYHA class III/IV compared to only 1 patient in class III at follow up (p=0.001). GroupII-Improvement in NYHA functional class from IV to III in 1 patient while the other remained in class III.
Quere et al, 2006, France	66 patients with low gradient (MPG<40mmHG), severe aortic stenosis (AVA< 1cm2) with an EF < 40% prospectively enrolled in (2) underwent AVR after dobutamine stress evaluation. Preoperative contractile reserve present in 46 patients (group I; 70%) and absent in 20 patients (group II 30%). Left ventricular ejection fraction calculated in all 66 patients before AVR and after the 30 day post operative period. Follow up clinical data obtained in all patients at a mean interval of 26+ 20 months.	Sub analysis of a prospective cohort study (level 2b)	Operative Mortality	Group I – 3 of 50 (6%). Group II – 10 of 30 (30%)	Well performed prospective cohort study (The French Multicentre study on low gradient AS)
			Postoperative functional improvement in those who survived	Group I-96% (44/46) improved by > 1 functional class and 59% (27/46) improved by > 2 functional classes after AVR. Group II-90% (18/20) ) improved by > 1 functional class (p=0.35 versus group 1) and 55%(11/20) improved by > 2 functional classes after AVR(p=0.50 versus group I).
			Postoperative improvement in ejection fraction in those who survived.	Group I-LVEF increased from 28+ 6% to 47+ 11% (p<0.0001) with a mean increase of 19+10%. Group II-LVEF increased from 31+ 6% to 48+ 11% (p=0.0001) with a mean increase of 17+11%.
			Postoperative survival at 2 years assuming operative survival	Group I- 92+7% (p=0.63). Group II-90+5%
Nishimura et al, 2002, USA	32 patients with low-output, low-gradient aortic stenosis and EF<40% subjected to Dobutamine stress testing in the catheterization laboratory. Based on the results of the above, 21 patients underwent AVR. Patients who had AVR divided into 2 groups on the basis of presence or absence of a contractile response to dobutamine infusion-group I (n=15) with >20% increase in stroke volume and group II(n=6) with < 20% increase in stroke volume.	Cohort study (Level 2b)	Peri-operative mortality	Group I- 7%-1 of 15 patients. Group II- 33%-2 of 6 patients.	Very small number of patients –only 6 patients in the group with no contractile reserve that underwent AVR. Observational study
			Late deaths	Group I-13.3%-2 of 15 patients- both non-cardiac . Group II-33%-2 of 6 patients -both cardiac-from heart failure at months 25 and 34 .
			Post operative functional improvement	Group I- all 12 in NYHA I-II. Group II- 2 in NYHA I-II.
Bergler-Klein et al, TOPAS Study, 2007, Austria	2002 to 2005 , 69 patients with low flow AS(EOA<0.6 cm2/m2 , mean grad <40mmHg, LVEF <40%), grouped into truly severe or pseudosevere AS by EOA <1.0 cm2 on dobutamine stress. Contractile reserve defined as an increase of SV >20%. BNP measured at regular intervals Surgery or medical therapy at discretion of physicians (29 AVR) 2 year follow up	Prospective Cohort study. (Level 2b)	Mortality	9 of 29 who had AVR (31%). 6 of 20 who had AVR with TS AS (30%). 3 of 9 who had AVR with PS AS (33%) 11 of 40 medically treated pts (27%) 2 of 9 med treated TS AS (22%). 9 of 31 med treated PS AS (29%)	The operative survival was not explicitly given for the subgroup with poor contractile reserve. This is (understandably) a small study for the sub-analyses performed
			BNP relationship to 30 day mortality in operated AS	19% if BNP>550pg/ml 8% if BNP <550pg.ml
			Pts with poor or no contractile reserve (n=32)	50% mortality in high BNP group. 100% mortality in low BNP group 1 year survival in patients with poor contractile reserve as as good as those with reserve as long as BNP <550pg/ml
Bonnow et al, of Cardiology/ACC/AHA/Clinical Practice Guideline, 2006, USA	Systematic review of a wide range of issues in valvular heart disease This review updated a previous review conducted in 1998	Systematic review (level 1a)	Guideline recommendations	Patients in whom stroke volume fails to increase with dobutamine (less than 20% increase) appear to have a very poor prognosis with either medical or surgical therapy Dobutamine stress echocardiography is reasonable to evaluate patients with low-flow/low-gradient AS and LV dysfunction. (Level of Evidence: B) Cardiac catheterization for hemodynamic measurements with infusion of dobutamine can be useful for evaluation of patients with low-flow/low-gradient AS and LV dysfunction. (Level of Evidence: C)	Only 2 references given in support of this recommendation.
Vahania et al, European Society of Cardiology task force guidelines on management of VHD, 2007, USA,	Systematic review of a wide range of issues in valvular heart disease	Systematic review (level 1a)	AVR in patients with severe aortic stenosis and no contractile reserve on stress testing	Patients in whom stroke volume fails to increase with dobutamine (less than 20% increase) appear to have a very poor prognosis with either medical or surgical therapySurgery can, nonetheless, be performed in these patients but decision-making should take into account clinical condition ( in particular, the presence of comorbidity), degree of valve calcification, extent of coronary disease, and feasibility of revascularisation.	Only 1 reference given in support of this recommendation

Comment(s)

Low gradient low flow aortic stenosis is defined by the American Heart Association as aortic stenosis with an effective aortic area less than 1 cm2, left ventricular ejection fraction less than 40% and mean transaortic pressure gradient of less than 30 mmHg. Assessment by dobutamine stress testing is essential to verify that the reduced effective orifice area is in fact severe rather than an effect of low flow on a mild or moderately stenosed valve[deFilippi]. Contractile reserve on dobutamine stress testing is defined by an increase in the systolic velocity integral or stroke volume by at least 20% during dobutamine infusion. Aortic valve replacement is recommended by the AHA for patients with low gradient, low flow aortic stenosis with contractile reserve (Class I: Level of evidence C). For patients without contractile reserve, the most comprehensive studies have been performed by the French multicentre study on low gradient aortic stenosis by Quere, Monin and colleagues. In the study by Monin et al in 2001, the perioperative mortality of patients without contractile reserve undergoing AVR was about 50% but the number of patients in this subgroup was only 6, and no definitive conclusions could be reached. In Monin's largest study published in 2003 involving 136 patients, Kaplan-Meier analysis of patients without contractile reserve showed a 2-year survival rate of 35% of those undergoing AVR and 15% treated medically. The most recent report by Quere et al where 20 patients without contractile reserve had an AVR, concluded that LV dysfunction and functional status can improve significantly after AVR even in patients with no contractile reserve although their operative mortality is around 30%. In a study by Nishimura et al, about one third of the patients without contractile reserve died perioperatively while another third died at months 25 and 34. Again the number of patients in this subgroup without contractile reserve who underwent AVR was very small-6, statistically not significant. The Topas Study (Truly Or Pseudosevere Aortic Stenosis)found in a cohort study of 69 patients, of whom 29 had an aortic valve replacement that poor contractile reserve was not a surgical predictor of mortality compared to patients with contractile reserve as long as the BNP was less than 550pg/ml. This was however a very small subset analysis. The American Heart Association guidelines state that the mortality is very high in patients with no contractile reserve either with or without surgery. The European Society of Cardiology agree with this but also state that surgery can be performed but should take into account the patient’s co-morbidities.

Clinical Bottom Line

It is clear that patients with severe aortic stenosis and a contractile reserve of less than 20% improvement in stroke volume on dobutamine stress testing have a very poor prognosis of only 10-20% at 2 years. Heart transplant would offer the best chance of survival to those eligible but for those not eligible, a surgical option should not be discounted for selected patients. The operative mortality is however around 30% but the French Multicentre study on low gradient aortic stenosis has shown that if the patient survives there is likely to be an improvement in symptoms and ejection fraction. Thus absence of contractile reserve on stress testing does not exclude myocardial recovery after surgery, although it is a strong predictor for operative mortality. It should be noted that surgery has only been reported in very few of these patients to date. B-natriuretic peptide has also been suggested as a further marker of better prognosis in these high risk patients in one small study.

References

1. deFilippi CR, Willett DL, Brickner ME, Appleton CP, Yancy CW, Eichhorn EJ, Grayburn PA. Usefulness of dobutamine echocardiography in distinguishing severe from nonsevere valvular aortic stenosis in patients with depressed left ventricular function and low transvalvular gradients. American Journal of Cardiology 1995;75(2):191-4.
2. Monin JL, Quere JP, Monchi M, Petit H, Baleynaud S, Chauvel C, Pop C, Ohlmann P, Lelguen C, Dehant P, Tribouilloy C, Gueret P. Low-gradient aortic stenosis: operative risk stratification and predictors for long-term outcome: a multicenter study using dobutamine stress hemodynamics.[see comment]. Circulation 2003;108(3):319-24.
3. Monin JL, Quere JP, Monchi M, Petit H, Baleynaud S, Chauvel C, Pop C, Ohlmann P, Lelguen C, Dehant P, Tribouilloy C, Gueret P. Aortic stenosis with severe left ventricular dysfunction and low transvalvular pressure gradients: risk stratification by low-dose dobutamine echocardiography Journal of the American College of Cardiology 2001;37(8):2101-7.
4. Quere JP, Monin JL, Levy F, Petit H, Baleynaud S, Chauvel C, Pop C, Ohlmann P, Lelguen C, Dehant P, Gueret P, Tribouilloy C. Influence of preoperative left ventricular contractile reserve on postoperative ejection fraction in low-gradient aortic stenosis.[see comment]. Circulation 2006;113(14):1738-44.
5. Nishimura RA, Grantham JA, Connolly HM, Schaff HV, Higano ST, Holmes DR, Jr. Low-output, low-gradient aortic stenosis in patients with depressed left ventricular systolic function: the clinical utility of the dobutamine challenge in the catheterization laboratory.[see comment] Circulation 2002;106(7):809-13.
6. Bergler-Klein J, Mundigler G, Pibarot P, Burwash IG, Dumesnil JG, Blais C, Fuchs C, Mohty D, Beanlands RS, Hachicha Z, Walter-Publig N, Rader F, Baumgartner H. B-type natriuretic peptide in low-flow, low-gradient aortic stenosis: relationship to hemodynamics and clinical outcome: results from the Multicenter Truly or Pseudo-Severe Aortic Stenosis (TOPAS). Circulation 2007;115(22):2848-55.
7. Bonow RO, Carabello BA, Kanu C, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2006;114(5):e84-231.
8. Vahanian A, Baumgartner H, Bax J, Butchart E, Dion R, Filippatos G, Flachskampf F, Hall R, Iung B, Kasprzak J, Nataf P, Tornos P, Torracca L, Wenink Task Force on the Management of Valvular Hearth Disease of the European Society of Cardiology, ESC Committee for Practice Guidelines. Guidelines on the management of valvular heart disease: European Heart Journal 2007;28(2):230-68.