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Efficacy of Angiotensin Receptor Blocker Following aortIc Valve Intervention for Aortic STenOsis: a Randomized mulTi-cEntric Double-blind Phase II Study (ARISTOTE)

Primary Purpose

Aortic Valve Stenosis, Valsartan, Angiotensin Receptor Antagonists

Status
Withdrawn
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Valsartan
Placebo Oral Tablet
Sponsored by
University Hospital, Limoges
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Aortic Valve Stenosis focused on measuring Aortic Valve Stenosis, Valsartan, Angiotensin Receptor Antagonists, Transcatheter Aortic Valve Replacement, Heart Valve Prosthesis Implantation, double-blind phase II study, left ventricular mass

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Men with age ≥18 years
  • Women at postmenopausal state as defined by absence of menses for the last 12 months without alternative medical cause.
  • Severe AS, defined according most recent guidelines (aortic valve area <1.0cm² or <0.6cm²/m² and aortic mean pressure gradient ≥40mmHg or aortic maximal velocity >4m/s, as assessed using transthoracic echocardiography [TTE]).
  • Indication for aortic valve intervention
  • Affiliation to the French Social Security system
  • Signed informed consent.

Exclusion Criteria:

  • Patients already under any Renin-Angiotensin-Aldosterone System blockers (RAASb) prior to randomization.
  • Concomitant coronary artery bypass graft or other valvular intervention
  • Other significant left-sided valvular heart diseases (≥moderate), even without concomitant procedure
  • Any contra-indication to CMR
  • Chronic kidney disease with estimated glomerular filtration rate (GFR) <30 ml/min
  • Prior or planned organ transplantation
  • Hyperkaliemia (kaliemia >5.5 mmol/L at inclusion visit)
  • Severe hepatic failure, biliary cirrhosis, cholestasis
  • Combined use of aliskiren and concomitant diabetes mellitus or renal failure with GFR<60mL/min/1.73m²
  • Low systolic blood pressure (<100mmHg)
  • History of angioedema
  • History of hypersensitivity or allergy to Angiotensin-II Receptor Blockers or excipient
  • Under legal authority.
  • Unwilling to consent

Secondary Exclusion Criteria:

  • Patients not under RAASb prior to randomization but who should benefit from this treatment to improve outcome:
  • Heart failure with reduced ejection fraction (<40%)
  • Coronary artery disease
  • Clinical peripheral artery disease
  • History of cerebrovascular disease
  • Uncontrolled hypertension despite the use of other therapeutic classes
  • Diabetes mellitus
  • Impossibility to perform randomization into the 9-day post-intervention period due to per procedural complication with prolonged stay in intensive cardiac care unit (including death).

Sites / Locations

  • Limoges university hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Valsartan

Placebo Oral Tablet

Arm Description

The active treatment is valsartan, an orally active, potent, and specific angiotensin II receptor antagonist. The treatment will be initiated (80 mg, daily) at 5±4 days following aortic valve intervention. The dose will be increased at 160 mg daily 13±2 days after aortic valve intervention and, if well tolerated, for the remaining period of the study.

The comparative treatment will be a placebo; tablets of valsartan and placebo have a similar appearance and administration mode. Patient in the control group will receive a placebo using the same protocol as the valsartan group.

Outcomes

Primary Outcome Measures

Indexed left ventricular mass
the 1-year change from baseline in indexed LVM after aortic valve intervention as assessed using cardiac magnetic resonance (CMR)

Secondary Outcome Measures

Left ventricular global longitudinal strain
The 1-year change from baseline in left ventricular global longitudinal strain quantified using CMR
Left ventricular global longitudinal strain
The 1-year change from baseline in Left ventricular global longitudinal strain quantified using transthoracic echocardiography (TTE)
Left atrial volume
The 1-year change from baseline in Left atrial volume quantified using CMR
Left atrial volume
The 1-year change from baseline in Left atrial volume quantified using TTE
Indexed left ventricular mass
the 1-year change from baseline in indexed LVM after aortic valve intervention as assessed using TTE (real-time 3D)
Native T1
the 1-year change from baseline in native T1 using CMR
Rate of late gadolinium enhancement (LGE)
the 1-year change from baseline in rate of LGE using CMR
Volume of late gadolinium enhancement (LGE)
the 1-year change from baseline in volume of LGE using CMR
Extra cellular volume
The 1-year change from baseline in extra cellular volume using CMR
Indexed interstitial volume
The 1-year change from baseline in Indexed interstitial volume using CMR
Electrocardiographic strain
The 1-year change from baseline in Electrocardiographic strain
Left ventricular ejection fraction
The 1-year change from baseline in Left ventricular ejection fraction using CMR
Left ventricular ejection fraction
The 1-year change from baseline in Left ventricular ejection fraction using TTE
Peak exercise VO2
The 1-year measurement of Peak exercise VO2
VE/VCO2 ratio
The 1-year measurement of VE/VCO2 ratio
Maximal load
The 1-year maximal load reached
New-York heart association functional class
The 1-year assessment of New-York heart association functional class
Exercise oscillatory ventilation rate
The 1-year quantification of exercise oscillatory ventilation rate
Nt-pro Brain natriuretic peptide
The 1-year change from baseline in level of Nt-pro Brain natriuretic peptide using immunoassay
Plasma cardiac troponin I
The 1-year change from baseline in concentration of Plasma cardiac troponin I using high-sensitivity assay
Incidence of treatment-Emergent Adverse Events
Clinical occurrence of adverse events (AEs) and serious adverse events (SAEs) during the duration of the study period ending month 13

Full Information

First Posted
October 17, 2017
Last Updated
March 15, 2023
Sponsor
University Hospital, Limoges
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1. Study Identification

Unique Protocol Identification Number
NCT03315832
Brief Title
Efficacy of Angiotensin Receptor Blocker Following aortIc Valve Intervention for Aortic STenOsis: a Randomized mulTi-cEntric Double-blind Phase II Study
Acronym
ARISTOTE
Official Title
Efficacy of Angiotensin Receptor Blocker Following aortIc Valve Intervention for Aortic STenOsis: a Randomized mulTi-cEntric Double-blind Phase II Study
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Withdrawn
Why Stopped
problem of faisability
Study Start Date
January 2, 2023 (Anticipated)
Primary Completion Date
July 2, 2025 (Anticipated)
Study Completion Date
July 2, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Limoges

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Aortic stenosis (AS) is the most frequent valvular heart disease in Western countries, with increasing prevalence. Recent guidelines recommend aortic valve intervention (surgical aortic valve replacement [SAVR] or transcatheter aortic valve replacement [TAVR]) in severe AS, as soon as symptoms or left ventricular (LV) dysfunction occur, in order to improve clinical outcome and achieve LV mass (LVM) regression. The highest amount of LVM regression is obtained during the first year. Nevertheless, there is heterogeneity in LV remodeling and residual LV hypertrophy is associated with poorer postoperative improvement in cardiac function and morphology. Incomplete regression of LV hypertrophy at 12 months after SAVR is a powerful predictor of adverse outcome. Yet, the use of specific pharmacological therapy to improve postoperative LVM regression could be an appealing therapeutic option after aortic valve intervention. Renin-angiotensin-aldosterone system blockers (RAASb) and more particularly angiotensin-II receptor blockers (ARBs) are efficient in reducing LVM in hypertensive patients, as emphasized by several meta-analyses. In addition, ARBs improve myocardial relaxation, diastolic function, decreased hypertrophy and may have anti-fibrotic effects. In a recent retrospective study from our group, RAASb prescription after SAVR was associated with increased survival, but confirmation through a randomized trial is mandatory. In a prospective randomized single-center study, the use of candesartan was associated both with LV and LA remodeling as compared to the conventional management. Nevertheless, these results are based on echocardiographic data, which is not the gold standard for the assessment cardiac remodeling, and no placebo or active comparator was tested to control the impact of ARBs in these patients. The primary objective of this Phase II study is to investigate the efficacy of valsartan, introduced postoperatively, as compared to placebo, on 1-year changes in indexed LVM, as assessed by CMR, in patients undergoing aortic valve intervention (SAVR or TAVR) for AS. The secondary objectives are to compare the efficacy of valsartan vs. placebo in terms of one-year changes (difference from baseline) in cardiac function and in cardiac morphology, one-year exercise capacity and one-year changes in biomarkers related to cardiac function. In addition, the assessment of the safety of valsartan will also be considered as secondary objective. The ARISTOTE trial is a multicenter prospective phase II, randomized, double-blind study including patients with the diagnosis of severe AS and indication for valve intervention. The active treatment is valsartan, an orally active, potent, and specific angiotensin II receptor antagonist. Patients will be randomized between 2 groups (valsartan versus placebo) and the treatment will be initiated (80 mg daily) at 5±4 days following aortic valve intervention. The comparative treatment will be a placebo; tablets of valsartan and placebo have a similar appearance and administration mode. Patient in the control group will receive a placebo using the same protocol as the valsartan group. The patients will be cautiously monitored and any adverse events will be collected. The dose will be increased at 160 mg daily 13±2 days after aortic valve intervention and, if well tolerated, for the remaining period of the study. The tolerance will be regularly assessed and dose adjusted according to a pre-specified algorithm.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Aortic Valve Stenosis, Valsartan, Angiotensin Receptor Antagonists, Transcatheter Aortic Valve Replacement, Heart Valve Prosthesis Implantation, Hypertrophy, Left Ventricular
Keywords
Aortic Valve Stenosis, Valsartan, Angiotensin Receptor Antagonists, Transcatheter Aortic Valve Replacement, Heart Valve Prosthesis Implantation, double-blind phase II study, left ventricular mass

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Patients with the diagnosis of severe AS and indication for valve intervention (i.e. SAVR or TAVR) fulfilling all inclusion/exclusion criteria will be randomized using 1:1 ratio.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Valsartan
Arm Type
Experimental
Arm Description
The active treatment is valsartan, an orally active, potent, and specific angiotensin II receptor antagonist. The treatment will be initiated (80 mg, daily) at 5±4 days following aortic valve intervention. The dose will be increased at 160 mg daily 13±2 days after aortic valve intervention and, if well tolerated, for the remaining period of the study.
Arm Title
Placebo Oral Tablet
Arm Type
Placebo Comparator
Arm Description
The comparative treatment will be a placebo; tablets of valsartan and placebo have a similar appearance and administration mode. Patient in the control group will receive a placebo using the same protocol as the valsartan group.
Intervention Type
Drug
Intervention Name(s)
Valsartan
Intervention Description
The active treatment is valsartan, an orally active, potent, and specific angiotensin II receptor antagonist. The treatment will be initiated (80 mg, daily) at 5±4 days following aortic valve intervention. The dose will be increased at 160 mg daily 13±2 days after aortic valve intervention and, if well tolerated, for the remaining period of the study.
Intervention Type
Drug
Intervention Name(s)
Placebo Oral Tablet
Intervention Description
The comparative treatment will be a placebo; tablets of valsartan and placebo have a similar appearance and administration mode. Patient in the control group will receive a placebo using the same protocol as the valsartan group.
Primary Outcome Measure Information:
Title
Indexed left ventricular mass
Description
the 1-year change from baseline in indexed LVM after aortic valve intervention as assessed using cardiac magnetic resonance (CMR)
Time Frame
Day 0 to Year 1
Secondary Outcome Measure Information:
Title
Left ventricular global longitudinal strain
Description
The 1-year change from baseline in left ventricular global longitudinal strain quantified using CMR
Time Frame
Day 0 to Year 1
Title
Left ventricular global longitudinal strain
Description
The 1-year change from baseline in Left ventricular global longitudinal strain quantified using transthoracic echocardiography (TTE)
Time Frame
Day 0 to Year 1
Title
Left atrial volume
Description
The 1-year change from baseline in Left atrial volume quantified using CMR
Time Frame
Day 0 to Year 1
Title
Left atrial volume
Description
The 1-year change from baseline in Left atrial volume quantified using TTE
Time Frame
Day 0 to Year 1
Title
Indexed left ventricular mass
Description
the 1-year change from baseline in indexed LVM after aortic valve intervention as assessed using TTE (real-time 3D)
Time Frame
Day 0 to Year 1
Title
Native T1
Description
the 1-year change from baseline in native T1 using CMR
Time Frame
Day 0 to Year 1
Title
Rate of late gadolinium enhancement (LGE)
Description
the 1-year change from baseline in rate of LGE using CMR
Time Frame
Day 0 to Year 1
Title
Volume of late gadolinium enhancement (LGE)
Description
the 1-year change from baseline in volume of LGE using CMR
Time Frame
Day 0 to Year 1
Title
Extra cellular volume
Description
The 1-year change from baseline in extra cellular volume using CMR
Time Frame
Day 0 to Year 1
Title
Indexed interstitial volume
Description
The 1-year change from baseline in Indexed interstitial volume using CMR
Time Frame
Day 0 to Year 1
Title
Electrocardiographic strain
Description
The 1-year change from baseline in Electrocardiographic strain
Time Frame
Day 0 to Year 1
Title
Left ventricular ejection fraction
Description
The 1-year change from baseline in Left ventricular ejection fraction using CMR
Time Frame
Day 0 to Year 1
Title
Left ventricular ejection fraction
Description
The 1-year change from baseline in Left ventricular ejection fraction using TTE
Time Frame
Day 0 to Year 1
Title
Peak exercise VO2
Description
The 1-year measurement of Peak exercise VO2
Time Frame
Year 1
Title
VE/VCO2 ratio
Description
The 1-year measurement of VE/VCO2 ratio
Time Frame
1 year
Title
Maximal load
Description
The 1-year maximal load reached
Time Frame
1 year
Title
New-York heart association functional class
Description
The 1-year assessment of New-York heart association functional class
Time Frame
1 year
Title
Exercise oscillatory ventilation rate
Description
The 1-year quantification of exercise oscillatory ventilation rate
Time Frame
1 year
Title
Nt-pro Brain natriuretic peptide
Description
The 1-year change from baseline in level of Nt-pro Brain natriuretic peptide using immunoassay
Time Frame
Day 0 to Year 1
Title
Plasma cardiac troponin I
Description
The 1-year change from baseline in concentration of Plasma cardiac troponin I using high-sensitivity assay
Time Frame
Day 0 to Year 1
Title
Incidence of treatment-Emergent Adverse Events
Description
Clinical occurrence of adverse events (AEs) and serious adverse events (SAEs) during the duration of the study period ending month 13
Time Frame
Day 1 to Month 13

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Men with age ≥18 years Women at postmenopausal state as defined by absence of menses for the last 12 months without alternative medical cause. Severe AS, defined according most recent guidelines (aortic valve area <1.0cm² or <0.6cm²/m² and aortic mean pressure gradient ≥40mmHg or aortic maximal velocity >4m/s, as assessed using transthoracic echocardiography [TTE]). Indication for aortic valve intervention Affiliation to the French Social Security system Signed informed consent. Exclusion Criteria: Patients already under any Renin-Angiotensin-Aldosterone System blockers (RAASb) prior to randomization. Concomitant coronary artery bypass graft or other valvular intervention Other significant left-sided valvular heart diseases (≥moderate), even without concomitant procedure Any contra-indication to CMR Chronic kidney disease with estimated glomerular filtration rate (GFR) <30 ml/min Prior or planned organ transplantation Hyperkaliemia (kaliemia >5.5 mmol/L at inclusion visit) Severe hepatic failure, biliary cirrhosis, cholestasis Combined use of aliskiren and concomitant diabetes mellitus or renal failure with GFR<60mL/min/1.73m² Low systolic blood pressure (<100mmHg) History of angioedema History of hypersensitivity or allergy to Angiotensin-II Receptor Blockers or excipient Under legal authority. Unwilling to consent Secondary Exclusion Criteria: Patients not under RAASb prior to randomization but who should benefit from this treatment to improve outcome: Heart failure with reduced ejection fraction (<40%) Coronary artery disease Clinical peripheral artery disease History of cerebrovascular disease Uncontrolled hypertension despite the use of other therapeutic classes Diabetes mellitus Impossibility to perform randomization into the 9-day post-intervention period due to per procedural complication with prolonged stay in intensive cardiac care unit (including death).
Facility Information:
Facility Name
Limoges university hospital
City
Limoges
ZIP/Postal Code
87042
Country
France

12. IPD Sharing Statement

Learn more about this trial

Efficacy of Angiotensin Receptor Blocker Following aortIc Valve Intervention for Aortic STenOsis: a Randomized mulTi-cEntric Double-blind Phase II Study

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