Management and prognosis of low gradient aortic stenosis

INTRODUCTION — Degenerative valvular heart disease (VHD) is common and is the third most frequent cause of cardiac disease after hypertension and coronary artery disease in developed countries with aging populations. Among patients with at least moderate VHD in developed countries, aortic valve stenosis (AS) is most common, followed by mitral regurgitation, then aortic regurgitation and finally mitral stenosis [1].

For appropriate diagnosis and management of AS, it is crucial to assess the severity of AS accurately as possible. However, the diagnosis and evaluation of AS are challenging due to a variety of pitfalls.

The management and prognosis of low gradient AS will be reviewed here. Clinical manifestations and diagnosis of low gradient AS and the clinical presentation and treatment of high gradient severe AS are discussed separately. (See "Clinical manifestations and diagnosis of low gradient severe aortic stenosis" and "Clinical manifestations and diagnosis of aortic stenosis in adults" and "Medical management of symptomatic aortic stenosis" and "Medical management of asymptomatic aortic stenosis in adults".)

MANAGEMENT

Approach to management — Management of patients with low gradient aortic stenosis AS starts with confirming the severity and type of AS. Subsequent steps include referral of patients with symptomatic true severe AS to a heart valve team for possible aortic valve replacement, monitoring asymptomatic patients, preventive measures to reduce risk of decompensation, and pharmacologic therapy to treat risk factors in asymptomatic patients and as a temporizing or palliative measure in symptomatic patients.

Confirmation of AS severity and type — Key steps in the management of patients with low gradient AS are to confirm the AS severity and type (see "Clinical manifestations and diagnosis of low gradient severe aortic stenosis", section on 'Diagnosis and evaluation'):

●Transthoracic echocardiography (TTE) is the first key test to determine the AS severity by measuring aortic valve area and peak and mean pressure gradients. However, when TTE is not contributive, transesophageal echocardiography should be considered to better visualize the aortic valve, the number of cusps, the degree of calcification, to better measure the LVOT diameter, and thus calculate the aortic valve area. The calcium scoring performed by noninjected computed tomography (CT) scan should be done whenever there is discrepancy between pressure gradients and aortic valve area, in case of classical low flow, low gradient (LFLG) AS or paradoxical LFLG AS.

●Confirmation of presence of true severe AS (or pseudosevere AS). Care should be taken to distinguish from symptomatic severe AS from moderate AS with symptoms due to other causes. When a patient is found to have severe AS by aortic valve area along with an unexpectedly low gradient, the possibility of measurement error should be considered, as discussed separately. (See "Clinical manifestations and diagnosis of low gradient severe aortic stenosis", section on 'Diagnosis and evaluation'.)

●If low gradient true severe AS is present, the next step is to determine which type. The types of low gradient severe AS are as follows:

•Classical LFLG AS, in which left ventricular ejection fraction (LVEF) is <50 percent and stroke volume index (SVi) is <35 mL/m².

•Paradoxical LFLG AS, in which LVEF is ≥50 percent and SVi is <35 mL/m².

•Normal flow, low gradient (NFLG) AS, in which LVEF is ≥50 percent and SVi is ≥35 mL/m².

Choice of therapy

Indications for referral to heart valve team — For patients with symptomatic low gradient AS, the following are indications for referral to a heart valve team for consideration of treatment options including aortic valve replacement (surgical aortic valve replacement [SAVR] or transcatheter aortic valve implantation [TAVI]) and palliative care:

●For symptomatic patients with LFLG severe AS with LVEF <50 percent (classical LFLG AS), with a low-dose dobutamine stress study that shows an aortic velocity ≥4 m/s (or mean pressure gradient ≥40 mmHg) with an valve area remaining ≤1.0 cm² at any dobutamine dose. (See 'For classical low flow, low gradient AS' below and 'Contractile reserve as a prognostic indicator' below.)

●For symptomatic patients with LFLG severe AS with LVEF <50 percent (classical LFLG AS) without flow reserve on low dose dobutamine stress study. (See 'For classical low flow, low gradient AS' below.)

●For symptomatic patients with low flow (SVi <35 mL/m), low gradient severe AS who are normotensive and have an LVEF ≥50 percent (paradoxical LFLG AS) with clinical, hemodynamic, and anatomic data supporting AS as the most likely cause of symptoms. (See 'For paradoxical low flow, low gradient AS' below.)

●For symptomatic patients with normal flow, low gradient severe AS with clinical, hemodynamic, and anatomic data supporting AS as the most likely cause of symptoms. (See 'For normal flow, low gradient AS' below.)

The first and third indications above are broadly consistent with the 2020 American College of Cardiology/American Heart Association and 2017 European Society of Cardiology (ESC) valve guidelines (table 1) [2,3]. The ESC guidelines also include a weak recommendation similar to the second recommendation. However, these major society guidelines do not provide specific recommendations for valve intervention for other groups of patients with low gradient AS.

Evidence on the impact of aortic valve replacement — The following (largely observational) evidence on the impact of aortic valve replacement (surgical in most studies) supports aortic valve replacement for patients with symptomatic severe AS with classical LFLG AS, paradoxical LFLG AS, or NFLG AS. In all studies, the conservative management group likely included patients with severe AS with severe comorbidities, so the benefit of aortic valve replacement was likely overestimated.

For classical low flow, low gradient AS — Aortic valve replacement is recommended in most patients with classical LFLG severe AS because observational studies have found that valve replacement is associated with better outcomes than continued medical therapy [4,5]. This was illustrated in a study of 95 patients who did or did not undergo aortic valve replacement [5]. Using propensity analysis, patients who underwent valve replacement had a significantly greater survival at one (82 versus 41 percent without surgery) and four years (78 versus 15 percent). The main predictor of improved survival was aortic valve replacement. (See "Indications for valve replacement for high gradient aortic stenosis in adults".)

However, patients with classical LFLG AS are at high risk for perioperative mortality with surgical aortic valve replacement, particularly when coronary artery disease is present. In a report of 52 patients with an LVEF ≤35 percent (mean 26 percent) and a transvalvular mean gradient of <30 mmHg (mean 23 mmHg), perioperative (30-day) survival was 79 percent, and overall survival at three and five years was 62 and 39 percent, respectively [6]. Survival at five years was much lower in patients with coronary artery disease (29 versus 71 percent). However, among the 30-day survivors, there were significant improvements in functional status and LVEF.

For paradoxical low flow, low gradient AS — For patients with paradoxical LFLG severe AS (LVEF ≥50 percent), a meta-analysis of largely observational studies found a significant survival benefit associated with aortic valve replacement compared with conservative management (hazard ratio [HR] 0.44, 95% CI 0.25-0.77 [7]; despite mixed results in underpowered individual studies [8,9]).

For normal flow, low gradient AS — For patients with NFLG severe AS, a meta-analysis of largely observational studies found a significant survival benefit associated with aortic valve replacement compared with conservative management (HR 0.48, 95% CI 0.28-0.83) [7].

Thus, the available evidence favors aortic valve replacement (surgical or transcatheter) in patients with severe NFLG AS. However, a prospective observational study (not included in the above meta-analysis) of 284 patients with symptomatic NFLG severe AS found that a strategy of watchful waiting (with aortic valve replacement performed when mean valve gradient was at least 40 mmHg) yielded no difference in mortality compared with early surgery [10]. Estimated actuarial eight-year mortality rates were not significantly different at 17.5 percent for the early AVR group and 27.5 for watchful observation group. For 83 propensity-score-matched pairs, the risk of mortality was not significantly different between the two groups (HR 1.13 for early AVR, 95% CI 0.55-2.35).

Evidence on the impact of transcatheter aortic valve implantation — The following evidence supports use of TAVI over conservative management in patients with inoperable LG severe AS and as an alternative to surgery in patients with high surgical risk LG severe AS. Of note, patients with LG severe AS generally face higher mortality rates following TAVI compared with patients with high gradient severe AS [11,12]. A meta-analysis including eight studies with a total of 12,589 patients with AS undergoing TAVI found that LG was independently associated with mortality at 12 months; LVEF did not affect this result [12].

Similarly, an observational study of outcomes following TAVI found that patients with classical LFLG AS had higher 30-day and mid-term (mean 13-month) mortality rates compared with patients with high gradient AS [11]. However, patients with paradoxical LFLG AS had mid-term (mean 13 month) mortality rates similar to those for high gradient AS despite having higher 30 mortality rates [11].

In the PARTNER trial of TAVI, both LF and LG were univariate predictors of one-year mortality but in multivariable analysis, LF was an independent predictor of mortality, while LVEF and pressure gradient were not [13]. The impact of TAVI in inoperable and high surgical risk cohorts with LF AS was examined:

●In the inoperable cohort, mortality rate was higher for patients with LF compared with those with NF, but mortality in both groups improved with TAVI compared with medical therapy (46 versus 76 percent with LF and 39 versus 54 percent with NF). Among the subset of LF patients with paradoxical LFLG AS, TAVR reduced one-year mortality from 66 to 35 percent and there was a trend to benefit at two years (77 versus 57 percent, p = 0.06).

●In the high-risk cohort, mortality rates were similar with TAVI and SAVR for low flow patients overall (40 and 38 percent), as well as for subgroups with classical LFLG AS and paradoxical LFLG AS.

Evaluation of potential candidates for aortic valve replacement

Referral to heart valve team — Patients with symptomatic severe AS should be referred to a multidisciplinary heart valve team for individualized risk/benefit assessment of treatment options, including SAVR, TAVI, and palliative care, as discussed in detail separately. (See "Choice of intervention for severe calcific aortic stenosis".)

Investigational pre-procedural tests — Additional testing has been proposed to aid risk stratification of candidates for aortic valve replacement but the effect of such testing on outcomes has not been established.

Contractile reserve as a prognostic indicator — In addition to its role in distinguishing between true severe and pseudo-severe stenosis, low-dose dobutamine echocardiography has been proposed as a means of risk stratifying patients with true severe AS as an aid in determining the appropriate therapy. However, the role of such risk stratification is uncertain since aortic valve replacement is generally indicated for patients with LFLG severe symptomatic AS.

In patients with classical LFLG AS (low gradient severe AS with LVEF <50 percent), the performance of low-dose dobutamine is useful to assess contractile reserve, assist risk stratification, and assess prognosis before valve intervention (SAVR or TAVI depending upon estimated surgical risk), although evidence suggests that such patients may benefit from valve surgery with LVEF improvement, irrespective of contractile reserve status [2,3,14].

Patients with LFLG severe AS with contractile reserve (defined as ≥20 percent increase in stroke volume or increase of more than 5 percent in LVEF or >10 mmHg increase in the mean transvalvular pressure gradient with dobutamine) have better short- and long-outcomes after surgery than when treated medically [4,15].

The utility of this approach was best illustrated in a study of 136 patients with symptomatic, severe AS (valve area ≤1 cm²), a low cardiac index (≤3 L/min per m²), and a mean transvalvular gradient ≤40 mmHg [4]. Contractile reserve (defined as an increase in stroke volume of ≥20 percent above baseline) was demonstrated by dobutamine infusion in 92 patients (68 percent). Aortic valve replacement was performed in 95 patients, including 64 with contractile reserve and 31 without. The following observations were made:

●Among the patients who underwent valve replacement, those who demonstrated contractile reserve had a lower perioperative mortality (5 versus 32 percent).

●The 64 patients with contractile reserve undergoing aortic valve replacement had a significantly lower three-year mortality rate than those who were managed medically (21 versus 79 percent).

●Patients without contractile reserve who were treated medically had a high mortality rate (eg, 89 percent at three years).

In a later report of 66 survivors of aortic valve replacement from the same multicenter study, the mean improvement in LVEF (19 versus 17 percent), the frequency of improvement of ≥1 New York Heart Association (NYHA) class (96 versus 90 percent) or ≥2 NYHA classes (59 versus 55 percent), and the likelihood of being NYHA class I or II (93 versus 85 percent) were similar in those with and without contractile reserve (table 2) [14]. This observation suggests that absence of contractile reserve alone should not be considered a contraindication to surgery [16]. (See "Clinical manifestations and diagnosis of low gradient severe aortic stenosis", section on 'Summary and recommendations'.)

Natriuretic peptides — A role for natriuretic peptide (eg, brain natriuretic peptide [BNP] or N-terminal proBNP [NT-proBNP]) level testing to risk stratify patients with LGLF AS has not been established. As described above, the TOPAS study, which enrolled 69 symptomatic (81 percent NYHA functional class II and III) patients with low flow (indexed aortic orifice area <0.6 cm²/m²) and low gradient (mean gradient ≤40 mmHg) AS with reduced LVEF (≤40 percent) [17]. One-year survival was significantly lower in those patients with a plasma BNP ≥550 pg/mL compared with those with <550 pg/mL (47 versus 97 percent) in the entire cohort and in the 29 patients who underwent surgery (53 versus 92 percent). These findings are consistent with previous studies showing that outcome depends upon the severity of LV dysfunction and HF. However, plasma BNP will rarely affect clinical decision-making because all of these patients benefit from aortic valve replacement, unless the surgical risk is prohibitive.

Measures of systolic function — Preliminary studies found that longitudinal function measured as mitral annular plane systolic excursion correlated with improvement in NYHA functional class (table 2) in patients with low or high gradient severe AS who underwent aortic valve replacement [18,19]. Patients with low gradient severe AS had decreased longitudinal function, higher degree of fibrosis on cardiac magnetic resonance imaging and worse clinical outcomes. Other studies using global longitudinal strain (GLS) have confirmed that GLS is decreased in patients with LFLG severe AS, and this decrease of GLS is correlated with outcome [20,21].

Role of palliative care — Patients with symptomatic severe AS should be referred to a heart valve team to estimate life expectancy if aortic valve replacement (SAVR or TAVI) is performed and the likelihood that SAVR or TAVI will improve the quality of life. If life expectancy with aortic valve replacement is ≤1 year or aortic valve replacement is not likely to improve the quality of life, we suggest referral for palliative care including pharmacologic and palliative care therapies for relief of symptoms, integration of care, and support to help families and caregivers cope with illness. (See "Medical management of symptomatic aortic stenosis", section on 'Role of palliative care' and "Palliative care for patients with advanced heart failure: Indications and systems of care" and "Palliative care for patients with advanced heart failure: Decision support and management of symptoms".)

General management — The following are key considerations in the general management of patients with AS, including patients with low gradient AS:

●Monitoring and follow-up – Asymptomatic patients with true severe or pseudo-severe AS should receive periodic monitoring by clinical evaluation and echocardiography to assess for symptoms and signs of worsening AS. The frequency of echocardiographic monitoring varies with the severity of AS. As an example, for asymptomatic patients with moderate AS, echocardiography is recommended every one to two years. (See "Medical management of asymptomatic aortic stenosis in adults", section on 'Serial evaluation'.)

●Routine preventive measures (such as influenza vaccination) are indicated, particularly since intercurrent illness can precipitate decompensation in patients with severe AS, as discussed separately. (See "Medical management of symptomatic aortic stenosis", section on 'Prevention and treatment of concurrent conditions'.)

●Patients with symptomatic severe AS should engage in only mild physical activity and should not participate in competitive sports. Recommendations for athletes with asymptomatic AS are discussed separately. (See "Medical management of asymptomatic aortic stenosis in adults", section on 'Physical activity and exercise' and "Medical management of symptomatic aortic stenosis", section on 'General considerations'.)

●Endocarditis prophylaxis is generally not indicated in patients with AS except in patients with high-risk conditions such as an existing prosthetic heart valve or a prior history of infective endocarditis. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures".)

Pharmacologic therapy

For patients with pseudosevere AS — For patients with pseudosevere AS, medical therapy consists of management of cardiovascular risk factors such as hypertension. (See "Overview of established risk factors for cardiovascular disease" and "Overview of hypertension in adults".)

For patients with true severe AS — In patients with LFLG (with reduced or preserved LVEF) or NFLG true severe AS, the role of medical management is limited since valve intervention (whether it is SAVR or percutaneous AVR) is required to address the primary process of aortic obstruction.

●For patients without symptoms – Truly asymptomatic patients with LFLG severe AS are rare, however. In such patients, medical management consists of addressing cardiovascular risk factors, including optimization of treatment of hypertension [2].

●For patients with symptoms who are candidates for SAVR or TAVI, pharmacologic therapy (eg, diuretics, vasodilators, or inotropes) should be used as a temporizing measure only as needed, since these interventions may destabilize the patient’s condition. (See "Medical management of symptomatic aortic stenosis", section on 'Medical management in patients awaiting aortic valve replacement'.)

●For patients with symptoms who are not candidates for SAVR or TAVI, palliative care includes cautious treatment of hypertension and optimization of volume status as discussed separately. (See "Medical management of symptomatic aortic stenosis", section on 'Management of adverse hemodynamic conditions and symptoms'.)

PROGNOSIS — Patients with classical LFLG severe aortic stenosis (AS) or paradoxical LFLG severe AS have higher mortality rates compared with patients with high gradient severe AS [13]. Patients with NFLG severe AS have mortality rates similar to those with high gradient severe AS. In contrast, patients with low gradient pseudo-severe AS have prognosis similar to that in patients with similar cardiovascular risk factors without AS [22].

●Classical LFLG AS – In a study of 107 patients with classical LFLG severe AS who were managed conservatively, five-year mortality was 43±11 percent in patients with pseudo-severe AS compared with 91±6 percent in patients with true severe AS and was 100 percent in patients without flow reserve [22].

●Paradoxical LFLG AS – Patients with paradoxical LFLG severe AS have worse outcomes compared with those with high gradient severe AS. In a study of 512 consecutive patients with severe AS (aortic valve area index ≤0.6 cm²/m²) and a normal LVEF (≥50 percent), the 181 (35 percent) with low flow (stroke volume index ≤35 mL/m²) had a significantly lower overall three-year survival compared with the 331 patients with normal flow (76 versus 86 percent) [23]. In the group with low flow, mean left ventricular (LV) mass and relative wall thickness were elevated consistent with concentric LV hypertrophy, and stroke volume was small (due to reduced LV end-diastolic volumes), which resulted in a relatively low pressure gradient. Symptom status was not reported in this study, but outcomes in both flow groups were better with surgical compared with medical therapy.

●Normal flow, low gradient AS – A meta-analysis found that mortality rates among patients with NFLG severe AS overlap those for patients with HG AS and are lower than those among patients with paradoxical LFLG AS [7].

●Pseudosevere LFLG AS – In a study that included 29 patients with pseudo-severe AS managed conservatively, survival in these patients was similar to that of a propensity-matched group of patients with heart failure without AS [22].

Patients with low gradient true severe AS are also at increased risk compared with patients with high gradient severe AS when undergoing aortic valve replacement. The morbidity and mortality of patients with low gradient AS undergoing aortic surgery are considerable [24,25]. As an example, a retrospective study of patients with severe AS undergoing isolated SAVR reported similar in-hospital mortality rates for LFLG and normal flow high gradient AS (2 and 1 percent) [26]. However, patients with LFLG AS had higher one- and five-year mortality rates compared with patients with normal flow, high gradient AS (13 and 28 versus 4 and 16 percent). Also, patients with classical LFLG AS had higher one- and five-year mortality rates compared with patients with paradoxical LFLG AS (27 and 42 versus 6 and 20 percent).

Among patients with low gradient AS, the mortality risk following surgical aortic valve replacement is further increased in patients who also have coronary artery disease [6,27]. In a series of 630 patients with AS undergoing valve replacement, those with a peak-to-peak systolic pressure gradient >125 mmHg had the best postoperative survival, while those with a gradient <35 mmHg had the worst [28]. Outcomes following surgical aortic valve replacement and transcatheter aortic valve implantation are discussed above.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac valve disease".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Aortic stenosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Management of patients with low gradient aortic stenosis (AS) includes confirming the severity (true severe versus pseudo-severe) and type of AS, referral of patients with symptomatic true severe AS to a heart valve team for possible aortic valve replacement, monitoring asymptomatic patients, preventive measures to reduce risk of decompensation, and pharmacologic therapy to treat risk factors in asymptomatic patients and as a temporizing or palliative measure in symptomatic patients. (See 'Approach to management' above and 'General management' above.)

●The types of low gradient severe AS are as follows (see 'Confirmation of AS severity and type' above and "Clinical manifestations and diagnosis of low gradient severe aortic stenosis", section on 'Diagnosis and evaluation'):

•Classical low flow, low gradient (LFLG) AS in which left ventricular ejection fraction (LVEF) is <50 percent.

•Paradoxical LFLG AS in which LVEF is ≥50 percent and stroke volume index (SVi) is <35 mL/m².

•Normal flow, low gradient (NFLG) AS in which LVEF is ≥50 percent and SVi is ≥35 mL/m².

●We suggest the following as indications for referral to a heart valve team to assess treatment options including aortic valve replacement (transcatheter aortic valve implantation [TAVI] or surgical aortic valve replacement [SAVR]) and palliative care, however, in most of patients with significant AS, there is no role of medical therapy (see 'Indications for referral to heart valve team' above):

•For symptomatic patients with LFLG severe AS with LVEF <50 percent (classical LFLG AS), with a low-dose dobutamine stress study that shows an aortic velocity ≥4 m/s (or mean pressure gradient ≥40 mmHg) with an valve area remaining ≤1.0 cm² at any dobutamine dose (Grade 2C). (See 'For classical low flow, low gradient AS' above.)

•For symptomatic patients with LFLG severe AS with LVEF <50 percent (classical LFLG AS) without flow reserve on low dose dobutamine stress study (Grade 2C). (See 'For classical low flow, low gradient AS' above.)

•For symptomatic patients with low flow (SVi <35 mL/m), low gradient severe AS who are normotensive and have an LVEF ≥50 percent (paradoxical LFLG AS) with clinical, hemodynamic, and anatomic data supporting AS as the most likely cause of symptoms (Grade 2C). (See 'For paradoxical low flow, low gradient AS' above.)

•For symptomatic patients with normal flow, low gradient severe AS with clinical, hemodynamic, and anatomic data supporting AS as the most likely cause of symptoms (Grade 2C). (See 'For normal flow, low gradient AS' above.)

●For patients with symptomatic low gradient severe AS (classical LFLG, paradoxical LFLG, or normal flow, low gradient), observational data suggest that aortic valve replacement (SAVR or TAVI) may improve survival. (See 'Evidence on the impact of aortic valve replacement' above and 'Evidence on the impact of transcatheter aortic valve implantation' above.)

●Patients with classical LFLG severe AS or paradoxical LFLG severe AS have higher mortality rates compared with patients with high gradient severe AS. Patients with NFLG severe AS have mortality rates similar to those with high gradient severe AS. In contrast, patients with low gradient pseudo-severe AS have prognosis similar to that in patients with similar cardiovascular risk factors without AS. (See 'Prognosis' above.)

ACKNOWLEDGMENTS

The UpToDate editorial staff acknowledges and Catherine Otto, MD, who contributed to earlier versions of this topic review.

The UpToDate editorial staff also acknowledges William H Gaasch, MD (deceased), who contributed to earlier versions of this topic review.