Clinical trial NCT03315832: Efficacy of Angiotensin Receptor Blocker Following aortIc Valve Intervention for Aortic STenOsis: a Randomized mulTi-cEntric Double-blind Phase II Study
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
Overall status: WITHDRAWN
Phase: PHASE2
PHASE3
Conditions: 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
Lead sponsor: University Hospital, Limoges
Sponsor class: OTHER
First posted: 2017-10-20
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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.


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).

Primary outcomes:
measure: Indexed left ventricular mass
timeFrame: Day 0 to Year 1
Secondary outcomes:
measure: Left ventricular global longitudinal strain
timeFrame: Day 0 to Year 1
measure: Left ventricular global longitudinal strain
timeFrame: Day 0 to Year 1
measure: Left atrial volume
timeFrame: Day 0 to Year 1
measure: Left atrial volume
timeFrame: Day 0 to Year 1
measure: Indexed left ventricular mass
timeFrame: Day 0 to Year 1
measure: Native T1
timeFrame: Day 0 to Year 1
measure: Rate of late gadolinium enhancement (LGE)
timeFrame: Day 0 to Year 1
measure: Volume of late gadolinium enhancement (LGE)
timeFrame: Day 0 to Year 1
measure: Extra cellular volume
timeFrame: Day 0 to Year 1
measure: Indexed interstitial volume
timeFrame: Day 0 to Year 1
measure: Electrocardiographic strain
timeFrame: Day 0 to Year 1
measure: Left ventricular ejection fraction
timeFrame: Day 0 to Year 1
measure: Left ventricular ejection fraction
timeFrame: Day 0 to Year 1
measure: Peak exercise VO2
timeFrame: Year 1
measure: VE/VCO2 ratio
timeFrame: 1 year
measure: Maximal load
timeFrame: 1 year
measure: New-York heart association functional class
timeFrame: 1 year
measure: Exercise oscillatory ventilation rate
timeFrame: 1 year
measure: Nt-pro Brain natriuretic peptide
timeFrame: Day 0 to Year 1
measure: Plasma cardiac troponin I
timeFrame: Day 0 to Year 1
measure: Incidence of treatment-Emergent Adverse Events
timeFrame: Day 1 to Month 13
Other outcomes:
Locations:
city: Limoges
country: France
facility: Limoges university hospital
Study officials:
References: