Transcatheter Aortic Valve Replacement in Severe Low Flow, Low Gradient Aortic Stenosis: the Multicenter LOW-TAVR Registry
Conditions: Low Flow, Low Gradient Aortic Stenosis
Sponsor: University of Salerno

Ver 1.0 of 12/02/2024 
 
“Transcatheter aortic valve replacement in severe low ﬂow low gradient aortic stenosis: 
the multicenter LOW-TAVR registry” 
Principal Investigator (PI): 
Prof. Gennaro Galasso 
Steering Committee: 
Angelo Silverio (statistical analysis) 
Michele Bellino (statistical analysis) 
Germano Jr. Ferruzzi 
Giovanni Granata (data management and statistical analysis) 
AGiliation: 
Department of Medicine, Surgery, and Dentistry, University of Salerno, Baronissi, Salerno, Italy 
 
STUDY PROTOCOL 
Title: 
Transcatheter aortic valve replacement in severe low ﬂow low gradient aortic stenosis: the 
multicenter LOW-TAVR registry 
Clinical Phase: 
Observational registry 
Coordinating Center: 
A.O.U. San Giovanni di Dio e Ruggi d'Aragona, Salerno 
Principal Investigator: 
Gennaro Galasso, MD, PhD 
Department/Institution: 
Cardio-Thoracic-Vascular Department, A.O.U. San Giovanni di Dio e Ruggi d'Aragona, Salerno, 
Italy 
Study Duration: 
20 years (01.01.2017 – 31.12.2037) 
GCP Statement: 
The study will be conducted in accordance with the ethical principles of the Declaration of 
Helsinki and is compliant with ICH Good Clinical Practice and regulatory requirements. 
Funding: 
The study will be conducted without ﬁnancial contributions from public or private funds. 
 

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SYNOPSIS 
Title of the Study: 
Transcatheter aortic valve replacement in severe low ﬂow low gradient aortic stenosis: the 
multicenter LOW-TAVR registry 
Study Duration: 
20 years (01.01.2017 – 31.12.2037) 
Study Design: 
Retrospective and partially prospective registry 
Study Objectives: 
To investigate the clinical characteristics and outcomes of patients with severe low ﬂow low 
gradient aortic stenosis (SA-LFLG) undergoing TAVR. 
The primary objective is to evaluate the rate of all-cause mortality or new hospitalizations due 
to heart failure exacerbation at the 1-year follow-up. 
Secondary objectives include the evaluation of periprocedural complications, in-hospital 
adverse events, and both short-term and long-term adverse events (30 days, 1 year, 2 years, 
and 5 years). 
Primary Endpoint: 
Composite endpoint of all-cause mortality and new hospitalizations for heart failure 
exacerbation at 1 year. 
Secondary Endpoints: 
• 
Periprocedural complications: complete atrioventricular block, stroke, acute 
myocardial infarction, acute aortic insuaiciency, cardiogenic shock, acute pulmonary 
edema, cardiac tamponade, aortic rupture. 
• 
In-hospital adverse events: major and minor bleeding, major and minor vascular 
complications, permanent pacemaker implantation, cardiogenic shock, myocardial 
infarction, stroke, and death. 
• 
Adverse events at 1-year follow-up: all-cause mortality, new hospitalizations for heart 
failure exacerbation, cardiovascular mortality, myocardial infarction, stroke, major and 
minor bleeding at 30 days, 1 year, 2 years, and 5 years. 
Number of Subjects: 
1500 
Number of Centers: 
6 
 
 

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ABBREVIATIONS LIST 
AS: Aortic stenosis 
AVA: Aortic valve area 
BNP: B-type natriuretic peptide 
BSA: Body surface area 
CK: Creatine kinase 
CK-MB: Creatine kinase – myocardial type 
ECG: Electrocardiogram 
EuroSCORE: European System for Cardiac Operative Risk Evaluation 
WBC: White blood cells 
HDL: High-density lipoproteins 
HF: Heart failure 
LDL: Low-density lipoproteins 
LFLG-AS: Low ﬂow low gradient aortic stenosis 
LVEF: Left ventricular ejection fraction 
sPAP: Systolic pulmonary arterial pressure 
SVi: Stroke volume index 
NYHA: New York Heart Association 
TAVR: Transcatheter aortic valve replacement 
VARC: Valve Academic Research Consortium 
CRF: Case report form 
GMP: Good manufacturing practice 
ICH: International Conference on Harmonization 
 
STUDY BACKGROUND 
According to current guidelines, severe low ﬂow low gradient aortic stenosis (LFLG-AS) is 
deﬁned by echocardiographic parameters as an aortic valve area (AVA) <1 cm² or an indexed 
AVA (AVAi) ≤0.6 cm²/m², a mean aortic gradient <40 mmHg, and a stroke volume index (SVi) 
<36 mL/m². Additionally, based on left ventricular ejection fraction (LVEF), patients with LFLG-
AS can be classiﬁed into a classic form (LVEF <50%) or a paradoxical form (LVEF ≥50%). 
Patients with LFLG-AS are estimated to account for approximately 15% of the overall 
population with severe aortic stenosis and are characterized by multiple comorbidities and 
high mortality, making this subgroup at high risk for traditional surgery. 
Currently, transcatheter aortic valve replacement (TAVR) is a safe and less invasive procedure 
than surgery and is recommended for patients at high surgical risk. However, in patients with 
LFLG-AS, TAVR may have a less favorable risk-beneﬁt ratio compared to high-gradient aortic 
stenosis. 

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The purpose of this study is to improve risk stratiﬁcation and prognostic evaluation in this 
high-risk population following TAVR through the creation of a large registry. 
BIBLIOGRAPHY 
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Vahanian A, Beyersdorf F, Praz F, Milojevic M, Baldus S, Bauersachs J, Capodanno D, 
Conradi L, De Bonis M, De Paulis R, Delgado V, Freemantle N, Gilard M, Haugaa KH, Jeppsson 
A, Jüni P, Pierard L, Prendergast BD, Sádaba JR, Tribouilloy C, Wojakowski W; ESC/EACTS 
Scientiﬁc Document Group. 2021 ESC/EACTS Guidelines for the management of valvular 
heart disease. Eur Heart J. 2022 Feb 12;43(7):561-632. doi: 10.1093/eurheartj/ehab395. 
Erratum in: Eur Heart J. 2022 Feb 18.  
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Clavel MA, Magne J, Pibarot P. Low-gradient aortic stenosis. Eur Heart J. 2016 Sep 
7;37(34):2645-57. doi: 10.1093/eurheartj/ehw096. Epub 2016 Mar 31. 
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Snir AD, Ng MK, Strange G, Playford D, Stewart S, Celermajer DS. Prevalence and 
Outcomes of Low-Gradient Severe Aortic Stenosis-From the National Echo Database of 
Australia. J Am Heart Assoc. 2021 Nov 16;10(22):e021126. doi: 10.1161/JAHA.121.021126. 
Epub 2021 Oct 30. 
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Clavel MA, Magne J, Pibarot P. Low-gradient aortic stenosis. Eur Heart J. 2016;37:2645-
2657. doi: 10.1093/eurheartj/ehw096 
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Pibarot P, Dumesnil JG. Low-ﬂow, low-gradient aortic stenosis with normal and 
depressed left ventricular ejection fraction. J Am Coll Cardiol. 2012;60:1845-1853. doi: 
10.1016/j.jacc.2012.06.051 
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Clavel MA, Berthelot-Richer M, Le Ven F, Capoulade R, Dahou A, Dumesnil JG, Mathieu 
P, Pibarot P. Impact of classic and paradoxical low ﬂow on survival after aortic valve 
replacement for severe aortic stenosis. J Am Coll Cardiol. 2015;65:645-653. doi: 
10.1016/j.jacc.2014.11.047 
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Meinertz T, Neumann T, Welz A, Mohr FW, Hamm CW; GARY Executive Board. TAVI for low-
ﬂow, low-gradient severe aortic stenosis with preserved or reduced ejection fraction: a 
subgroup analysis from the German Aortic Valve Registry (GARY). EuroIntervention. 2014 
Nov;10(7):850-9. doi: 10.4244/EIJV10I7A145. 
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Ribeiro HB, Lerakis S, Gilard M, Cavalcante JL, Makkar R, Herrmann HC, Windecker S, 
Enriquez-Sarano M, Cheema AN, Nombela-Franco L, Amat-Santos I, Muñoz-García AJ, Garcia 
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Szeto WY, Clavel MA, de Agustin A, Serra V, Schindler JT, Dahou A, Puri R, Pelletier-Beaumont 
E, Côté M, Pibarot P, Rodés-Cabau J. Transcatheter Aortic Valve Replacement in Patients With 
Low-Flow, Low-Gradient Aortic Stenosis: The TOPAS-TAVI Registry. J Am Coll Cardiol. 2018 
Mar 27;71(12):1297-1308. doi: 10.1016/j.jacc.2018.01.054. 

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Aortic Stenosis. JACC Cardiovasc Imaging. 2017 Feb;10(2):185-202. doi: 
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Aortic Valve Implantation: A Report From the SwissTAVI Registry. J Am Heart Assoc. 2023 Jun 
20;12(12):e029489. doi: 10.1161/JAHA.123.029489. Epub 2023 Jun 10. 
STUDY OBJECTIVES 
Although criteria for the diagnosis of LFLG-AS have been established, the clinical and 
anatomical characteristics, procedural strategy, and possible short- and long-term 
complications of LFLG-AS treated with TAVR in large patient cohorts are still not well deﬁned. 
There remain many questions regarding risk stratiﬁcation, accurate selection of patients for 
TAVR, and the prognostic framework for this speciﬁc high-risk population. Observing the 
natural history of patients with LFLG-AS who undergo TAVR may help us better understand 
this pathology and identify factors associated with poor prognosis. 
Therefore, we aim to study the clinical characteristics, incidence, risk factors, comorbidities, 
anatomical characteristics, procedural strategy, in-hospital complications after TAVR, gender 
diaerences, and prognosis (short- and long-term) of patients with LFLG-AS who undergo 
TAVR, as well as the peculiar characteristics of diaerent forms of LFLG-AS. 
 
STUDY POPULATION 
We intend to enroll 1500 patients diagnosed with LFLG-AS undergoing TAVR admitted to 
participating centers in Italy. 
 
 
 

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Inclusion Criteria 
Patients diagnosed with LFLG-AS as deﬁned by the criteria in the current European guidelines 
who undergo TAVR: 
Echocardiographic criteria for LFLG-AS: 
Aortic valve area <1 cm² or aortic valve area indexed to BSA ≤0.6 cm²/m² 
Mean aortic valve gradient <40 mmHg 
Maximum aortic valve velocity <4 m/s 
Stroke volume indexed to BSA <36 ml/m² 
The classical form is deﬁned by a left ventricular ejection fraction (LVEF) <50% 
The paradoxical form is deﬁned by preserved LVEF (≥50%) 
In patients with LVEF <50%, the diagnosis of LFLG-AS is conﬁrmed by dobutamine stress 
echocardiography to rule out the possibility of pseudo-severe aortic stenosis. 
In patients with LVEF ≥50%, the severity of aortic stenosis is conﬁrmed through the evaluation 
of the calcium volume of the native aortic valve via computed tomography (CT). 
Patients with LFLG-AS are candidates for TAVR through a multidisciplinary decision-making 
process (Heart Team) based on a comprehensive assessment of surgical risk according to the 
"European System for Cardiac Operative Risk Evaluation" (EuroSCORE II), as well as clinical, 
echocardiographic, and CT parameters. 
Modiﬁed from Vahanian A et al. ESC/EACTS Guidelines for the management of valvular heart 
disease. Eur Heart J. 2022 Feb 12;43(7):561-632. doi: 10.1093/eurheartj/ehab395. 
 
Exclusion Criteria 
Pseudo-severe LFLG-AS or failure to conﬁrm the severity of aortic stenosis according to the 
current criteria of the European guidelines 
LFLG-AS directed to medical therapy or subjected to surgery 
Pregnant or breastfeeding women 
 
STUDY DESIGN 
This is a spontaneous observational "non-proﬁt" retrospective and partly prospective registry 
that aims to enroll patients with a previous diagnosis (retrospective) and newly diagnosed 
(prospective) LFLG-AS treated with TAVR. 
 

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METHODS 
Study Population 
At least 1500 patients diagnosed with LFLG-AS treated with TAVR and admitted to 
participating centers. 
This population includes patients with a previous diagnosis made based on the diagnostic 
criteria according to the current European guidelines mentioned above, or patients with a new 
diagnosis. 
Parameters 
We intend to collect parameters from the clinical history, the TAVR procedure, and the 
subsequent clinical course of patients with LFLG-AS treated with TAVR. This information will 
be included in a speciﬁc data collection sheet. We will collect data on medical history, 
physical examination, laboratory parameters, and results from instrumental tests such as 
ECG, echocardiogram, coronary angiography, cardiac MRI, and/or cardiac CT, as well as the 
characteristics of the TAVR procedure. 
The accompanying symptoms will be classiﬁed according to the NYHA scale. The medical 
history will include classic cardiovascular risk factors (family history, obesity, smoking, 
hypertension, diabetes mellitus, lipid proﬁle), and known patient comorbidities will be 
documented. Regarding laboratory parameters, routine cardiac enzymes (troponin, BNP, CK, 
CK-MB), blood count (hemoglobin, WBC), electrolytes (sodium, potassium), renal function 
indices (creatinine, EGFR, and BUN), and lipid proﬁle (triglycerides, total cholesterol, HDL 
cholesterol, LDL cholesterol) will be considered. ECGs and echocardiograms at hospital 
admission and during the subacute period following TAVR will be analyzed. Coronary 
angiography parameters will be used for better characterization and extent of any 
concomitant coronary artery disease, according to the SYNTAX score. Pre-TAVR CT 
parameters will be collected to analyze anatomical factors, the TAVR procedural strategy, 
hemodynamic parameters, and details of acute phase management (resuscitation, aortic 
counterpulsation, respiratory failure), as well as in-hospital complications after TAVR, 
according to the Valve Academic Research Consortium (VARC) 3 criteria. 
All the parameters mentioned above are already part of routine clinical practice for this type 
of pathology, regardless of the study's objectives. In fact, the patient will not undergo 
additional tests, nor will there be any modiﬁcations in clinical and/or therapeutic 
management compared to current clinical evidence and care standards. 
The follow-up analysis will be conducted using a hospital database. We intend to 
subsequently contact the patients for telephone interviews to gather information on major 
adverse cardiac events (death, acute heart failure, myocardial infarction, stroke/transient 
ischemic attack, atrioventricular blocks, and permanent pacemaker or deﬁbrillator 
implantation, malignant ventricular arrhythmias) according to VARC 3 criteria, current 
pharmacological therapy, and cardiac, neurological, psychiatric, and oncological 

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comorbidities. The ﬁrst clinical and instrumental follow-up (ECG and echocardiography) will 
be conducted one month after the TAVR procedure and then every six months. 
All data will be collected using a speciﬁc data collection sheet and saved in an online data 
collection system approved according to GMP. All stored data, both related to the baseline 
enrollment time and the telephone and/or clinical follow-up, will be completely anonymized, 
and only the PI and authorized investigators will have access and use them. 
Cooperation 
In this project, the reference center (A.O.U. San Giovanni di Dio e Ruggi d’Aragona) will 
collaborate with several cardiovascular centers throughout Italy. The local ethics committees 
of each center will be responsible for patient participation in this partly retrospective and 
partly prospective analysis. 
Data Analysis 
The baseline and follow-up data of enrolled patients will be analyzed using descriptive 
statistics. Categorical variables will be analyzed using the chi-square test or Fisher's exact 
test, as appropriate. Continuous variables were analyzed for normality using the Shapiro-Wilk 
test. Depending on their distribution, continuous variables were expressed as mean ± 
standard deviation, or median and interquartile range (25th-75th IQR), as appropriate. An 
unpaired two-tailed t-test will be used to compare continuous variables between groups, and 
the chi-square test for comparison of categorical variables. 
A p-value <0.05 will be considered statistically signiﬁcant. 
The independent association with primary and secondary endpoints will be evaluated using 
binary logistic regression analysis. 
Statistical analyses will be performed using RStudio software (RStudio Team (2020). RStudio: 
Integrated Development for R. RStudio, PBC, Boston, MA URL http://www.rstudio.com/). 
 
PRIVACY PROTECTION 
All results will be used for the purposes of the study objectives. All data will be anonymized 
using a code for each patient. 
 
 
 
 
 

Ver 1.0 of 12/02/2024 
Study title: "Transcatheter aortic valve replacement in severe low ﬂow, low gradient 
aortic stenosis: the multicenter LOW-TAVR registry." 
The researchers declare no conﬂict of interest for this observational "non-proﬁt" 
study/registry and that no insurance coverage is required. 
 
Date, 12/02/24 
 
Approved with signature by: 
Gennaro Galasso MD, PhD