Renal Artery Stenting in Patients With Documented Resistant Hypertension and Atherosclerotic Renal Artery Stenosis (ANDORRA)

Study Overview
=================
Brief Summary
-----------------
The ANDORRA study is a, multicenter, prospective, open, randomized, controlled blinded endpoint trial (PROBE) comparing two treatment strategies (renal artery stenting + standardized and optimized medical treatment [SOMT] versus SOMT alone) of 12 months duration in patients with confirmed resistant hypertension (RH) and angiographically proven grade III unilateral or bilateral atherosclerotic renal artery stenosis (ARAS) ≥ 60%.

Detailed Description
-----------------
All eligible patients diagnosed with RH on office BP measurements and unilateral or bilateral ARAS ≥60% on a non-invasive test (CT-angiogram or MR-angiogram) will receive a standardized optimized triple antihypertensive treatment for 4 weeks. After 4 weeks, patients with confirmed RH by ABPM (daytime ABPM ≥ 135 or 85 mmHg) and no clinically significant increase in plasma creatinine from baseline (< 30%) will undergo a renal angiogram to confirm the degree of ARAS ≥60% in diameter. Immediately after the renal angiography, all patients will undergo flow fractional reserve (FFR) measurements. Once FFR measurements have been done and all criteria are met, patients will be randomized in the angiography room to either renal artery stenting + SOMT (stenting group) versus SOMT (control group) whatever the results of the FFR in a 1:1 ratio. Both groups will continue the SOMT during follow-up. The SOMT will be prescribed from the inclusion visit until the 6 month-visit after randomization. After randomization, the antihypertensive treatment will be adapted according to the results of home BP (HBP) at monthly visits starting 2 months after randomization. After the 6-month visit, the antihypertensive treatment adaptation will be left at the discretion of the physician in charge of the patient.

Official Title
-----------------
Optimum and Stepped Care Standardised Antihypertensive Treatment With or Without Renal Artery Stenting in Patients With Documented Resistant Hypertension and Atherosclerotic Renal Artery Stenosis. ANDORRA TRIAL

Conditions
-----------------
Hypertension, Hypertension Resistant to Conventional Therapy, Angiographically Proven Grade III Unilateral or Bilateral Atherosclerotic Renal Artery Stenosis (ARAS) Greater Than or Equal to 60 Percent

Intervention / Treatment
-----------------
* Device: Renal artery Angioplasty plus stenting.
* Drug: Anti hypertensive, statin and antiplatelet medication.


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age: 40 to 80 Years Men or women Supine office BP ≥ 140 and/or 90 mmHg at screening despite a stable medication regimen including full tolerated doses of 3 or more anti-hypertensive treatments of different classes, including a diuretic. Unilateral or bilateral ARAS of a main renal artery ≥60% diagnosed by renal CT- angiogram (or MR-angiogram if there is a contraindication to perform CT) performed in the year before One or two functional kidney(s) ≥ 70 mm in pole-to-pole length eGFR ≥ 20 ml/min/1.73 m² (MDRD formula) Signed informed consent Social insurance coverage Inclusion criteria for the renal angiogram procedure: - RH confirmed by daytime ABPM ≥ 135 or 85 mmHg after 1 month treatment with SOMT at Visit V1. Inclusion criteria for the randomization: Unilateral or bilateral ARAS of a main renal artery ≥ 60% confirmed on renal angiogram by Quantitative Vascular Analysis (QVA) Increase in plasma creatinine < 30% after 4-week SOMT Exclusion Criteria: Fibromuscular dysplasia of renal artery or other non-atherosclerotic renal artery stenosis Other secondary form of hypertension excluded on the basis of a clinical, hormonological and/or imaging work-up Restenosis after a previous renal angioplasty or stenting Only a stenosis of an accessory renal artery supplying <1/2 of the ipsilateral renal parenchyma Additional indication of ARAS stenting (Malignant hypertension, ≥ 30% increase in plasma creatinine after renin angiotensin system (RAS) blocker or after RAS blocker and diuretic administration, flash pulmonary edema) Kidney pole-to-pole length < 70 mm Vascular disease precluding access for stenting Abrupt vessel closure or dissection after diagnostic angiography Contraindication to renal artery stenting according the notice for use of the stents eGFR < 20 ml/min/1.73 m² (MDRD) History of transient ischemic accident (TIA) or cerebrovascular accident (CVA) during the 3 months prior to visit 1 History of acute heart failure or heart failure (NYHA class III-IV) within the 3 months prior to visit 1 History of myocardial infarction, unstable angina, coronary bypass or percutaneous coronary angioplasty during the 3 months prior to visit 1 Abdominal aortic aneurysm with indication for surgery or EVAR (Endovascular Aneurysm Repair) Known history of cholesterol embolism Brachial circumference of ≥ 42 cm Severe contrast media allergy, not amenable to pre-treatment Allergy to aspirin or clopidogrel Atrial fibrillation Comorbid condition causing life expectancy ≤ 3 years Unlikely to co-operate in the study and/or poor compliance anticipated by the investigator Participant not affiliated to the French social security Pregnancy or breastfeeding Guardianship for incapacity

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Renal artery stenting<br>Renal artery angioplasty plus stenting and standardized and optimized medication regimen. Patients are treated with renal artery stenting plus a standardized optimal medical treatment, including the antihypertensive treatment which is adapted every month starting two month after randomization on the basis of home BP monitoring results at follow-up visits. | Device: Renal artery Angioplasty plus stenting.<br>* renal artery stenting<br>* Other names: RA Stent;Drug: Anti hypertensive, statin and antiplatelet medication.<br>* Slow release indapamide 1.5 mg/d (or furosemide 40 mg/d if eGFR is < 30 mL/min/1.73m²) + irbesartan 300 mg/d + amlodipine 10 mg/d + aspirin 75 mg/d (or clopidogrel 75 mg/d in case of allergy or gastrointestinal intolerance to aspirin) + atorvastatin 20 mg/d. After randomization, bisoprolol 10 mg/d, prazosin 5 mg/d, and rilmenidine 1 mg/d and spironolactone 12.5 to 25 mg/d, will be sequentially added from months two to five in both groups if home blood pressure remains more than or equal to 135/85 mm Hg.<br>* Other names: SOMT;|
| Active Comparator: standardized and optimized medication regimen<br>Patients are treated with a standardized optimal medical treatment including the antihypertensive treatment which is adapted every month starting two month after randomization on the basis of home BP monitoring results at follow-up visits. | Drug: Anti hypertensive, statin and antiplatelet medication.<br>* Slow release indapamide 1.5 mg/d (or furosemide 40 mg/d if eGFR is < 30 mL/min/1.73m²) + irbesartan 300 mg/d + amlodipine 10 mg/d + aspirin 75 mg/d (or clopidogrel 75 mg/d in case of allergy or gastrointestinal intolerance to aspirin) + atorvastatin 20 mg/d. After randomization, bisoprolol 10 mg/d, prazosin 5 mg/d, and rilmenidine 1 mg/d and spironolactone 12.5 to 25 mg/d, will be sequentially added from months two to five in both groups if home blood pressure remains more than or equal to 135/85 mm Hg.<br>* Other names: SOMT;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change in diurnal systolic blood pressure assessed by ambulatory BP monitoring (ABPM) |  | Baseline to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events of renal artery stenting |  | Baseline to 12 months | 
| Change in average 24-hour and nighttime Systolic Blood Pressure by ABPM |  | Baseline to 12 months | 
| Change in average 24-hour, daytime and nighttime diastolic Blood Pressure by ABPM |  | Baseline to 12 months | 
| Change in Systolic/diastolic Blood Pressure by home blood pressure monitoring |  | Baseline to 12 months | 
| Change in office Systolic/diastolic Blood Pressure |  | Baseline to 12 months | 
| Antihypertensive medication score |  | Baseline to 12 months | 
| Detection of the drugs in urine by LC-MS/MS |  | Baseline to 12 months | 
| Renal artery restenosis in patients of the stenting group assessed by duplex ultrasound and/or renal CTA |  | Baseline to 12 months | 
| Adverse cardiovascular (CV) events |  | Baseline to 12 months | 
| Change in plasma creatinine and eGFR |  | Baseline to 12 months | 
| Clinical renal events: renal death, progressive renal insufficiency (i.e. need for dialysis), need for permanent renal replacement therapy, need of target vessel stenting in the SOMT group (number of crossovers) |  | Baseline to 12 months |