Clinical trial NCT02617238: Strategy for Preventing Cardiovascular and Renal Events Based on ARTErial Stiffness
Official title: Strategy for Preventing Cardiovascular and Renal Events Based on ARTErial Stiffness
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Hypertension
Keywords: arterial stiffness
cardiovascular risk
cardiovascular events
renal events
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
name: Fondation pour la Recherche en Hypertension Artérielle
First posted: 2015-11-30
Enrollment: 3000
Sex: ALL
Minimum age (years): 55
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Randomised two parallel groups multicenter study using a Prospective Randomised Open Blinded End-point design (PROBE), aiming at comparing the efficacy of a therapeutic strategy targeting the normalisation of arterial stiffness for reducing cardiovascular (CV) and renal events, in comparison with a classical therapeutic strategy implementing the European Society of Hypertension-European Society of Cardiology (ESH-ESC) Guidelines, in patients with essential hypertension and medium-to-very high CV risk.

Detailed description: The objective is to show that a therapeutic strategy targeting the implementation of international guidelines PLUS the normalisation of blood pression (BP \< 140 and 90 mmHg) plus the normalisation of arterial stiffness (measured every 6 months) Pulse Wave Velocity group (PWV group) reduces CV and renal events to a significantly greater extent than the sole implementation of Guidelines (conventional group, with PWV measurement at baseline and every 2 years).

Experimental design: Prospective Randomised Open Blinded Endpoint (PROBE) multicenter, two parallel groups, study.

Therapeutic strategy in the PWV group:

1. Use maximal recommended doses of angiotensin-converting-enzyme inhibitor (ACEIs) or Angiotensin II receptor blockers (ARBs) as first step treatment. And then adapt treatment to PWV values.
2. In second step, use combination therapy with Calcium channel blockers (CCBs)
3. Use diuretics in combination therapy, either as an alternative to CCBs in second step or as triple therapy in third step
4. Use, as fourth step, vasodilating beta-blockers (VD-BB) or spironolactone
5. In parallel, correct all CV risk factors according to ESH-ESC Guidelines, and reinforce treatment (hypolipidemic drugs, glucose lowering drugs, antiplatelets) if secondary prevention.

Therapeutic strategy in the conventional group: Apply the ESH-ESC Guidelines

Eligibility criteria: Inclusion Criteria:

* registration to the French social security system
* patients who did not specifically express their non willingness to participate

PLUS either A, B or C:

1. Patients with essential hypertension, aged 55 to 75 years old, both sexes

   * Grade 1 hypertension of more
   * Treated or not
   * Whatever the control of BP
   * Under primary of secondary prevention (more than 3 months stroke or myocard infarctus (MI), or stable angina or peripheral artery disease) PLUS at least 3 CV risk factors according to ESH-ESC 2007 guidelines or metabolic syndrome associating at least 2 of the following criteria

     * SBP/DBP over 130/85 mmHg
     * HDL-C \<1.0 mmol/l (0,4 g/l) (M) or \< 1.2 mmol/l (0,46 g/l) (F)
     * Triglycerides \>1,7 mmol/l (\>1,5 g/l)
     * Fasting blood glucose 5,6 - 6,9 mmol/l (1,02-1,25 g/l)
     * Waist circumference \> 102 cm (M) ou 88 cm (F) or Type 2 diabetes or Target organ damage, according to the definition of the ESH-ESC Guidelines for the Management of Hypertension or CV disease or chronic kidney disease
2. SBP \> 180 mmHg and/or DBP \> 110 mmHg
3. SBP \> 160 mmHg AND DBP \< 70 mmHg

Exclusion Criteria:

* Patients with ABPM or self-measurement normal without treatment (\<130 mmHg and 80 in the ABPM 24 or \<135 and 85 mmHg or daytime ABPM self-measurement of blood pressure)
* Patients with secondary hypertension (renal artery stenosis, pheochromocytoma, or hypermineralocortisism)
* Patients with hypertension secondary to diabetic nephropathy
* Patients aged under 55 or over 75 years,
* Low-risk CV patients
* Patients with severe chronic renal impairment creatinine clearance (MDRD) \<30ml / min / 1.73m2
* Patients with type I diabetes
* Patients with severe disease threatening the vital prognosis in the short and medium terms
* Patients who previously experienced a painful gynecomastia under spironolactone
* Patients with alcohol dependence or excessive consumption alcoholic beverages (at the judgement of the investigator)
* patients with accident history neurovascular, coronary insufficiency (coronary bypass surgery or percutaneous coronary intervention) not older than 3 month
* Patients with a history of acute heart failure or having open failure heart (NYHA class III-IV)
* Patients with unstable angina
* Auricular Fibrillation (AF) less than 6 months ago
* Patients with aortic stent
* Patients with known aneurysms of the abdominal aorta
* Patients with atrioventricular block second or third degree without pacemaker
* Patients having received organ transplant or placed on a waiting list for transplantation
* Patients with severe chronic inflammatory disease (rheumatoid arthritis; lupus; scleroderma ...)
* Patients with severe chronic infectious disease
* Patients who have had an MI less than 3 months ago
* Patients with stroke there are less than 3 months ago
* Patients with progression of peripheral arterial disease
* Patient whose pregnancy is known or which has no effective contraception if is of childbearing age, or if she is breastfeeding
* Patients who have expressed their opposition to participate in the protocol or have an inability to understand or follow the protocol
* The patients geographically too far from the place of investigation
* Patients already participating in other drug research protocol or Interventional

Primary outcomes:
measure: Number of cardiovascular and renal events
timeFrame: 4 years of follow-up
Secondary outcomes:
measure: Number of non-fatal myocardial Infarction
timeFrame: 4 years follow-up
measure: Number of non-fatal stroke
timeFrame: 4 years follow-up
measure: Number of adverse renal outcome (defined by chronic dialysis, kidney transplantation, or doubling of serum creatinine)
timeFrame: 4 years follow-up
measure: Number of hospitalization for any of the following causes: angioplasty or bypass surgery for coronary or peripheral vessel disease
timeFrame: 4 years follow-up
measure: Number of congestive heart failure
timeFrame: 4 years follow-up
measure: Number of aortic dissection
timeFrame: 4 years follow-up
measure: Carotid-femoral pulse wave velocity (PWV) value at the end of the study
timeFrame: 4 years follow-up
measure: Central systolic blood pressure value
timeFrame: 4 years follow-up
measure: Central pulse pressure value
timeFrame: 4 years follow-up
Other outcomes:
Locations:
city: Paris
country: France
facility: Clinical Investigation Center, Hopital Europeen Georges Pompidou
Study officials:
affiliation: Hopital Europen Georges Pompidou, Assistance publique Hopitaux de Paris
name: Stephane LAURENT, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hopital Europen Georges Pompidou, Assistance publique Hopitaux de Paris
name: Pierre BOUTOUYRIE, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Laurent S, Briet M, Boutouyrie P. Arterial stiffness as surrogate end point: needed clinical trials. Hypertension. 2012 Aug;60(2):518-22. doi: 10.1161/HYPERTENSIONAHA.112.194456. Epub 2012 Jun 25. No abstract available.
citation: Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, Pannier B, Vlachopoulos C, Wilkinson I, Struijker-Boudier H; European Network for Non-invasive Investigation of Large Arteries. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J. 2006 Nov;27(21):2588-605. doi: 10.1093/eurheartj/ehl254. Epub 2006 Sep 25.
citation: Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L, Rynkiewicz A, Schmieder RE, Boudier HA, Zanchetti A, Vahanian A, Camm J, De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL, Erdine S, Kiowski W, Agabiti-Rosei E, Ambrosioni E, Lindholm LH, Viigimaa M, Adamopoulos S, Agabiti-Rosei E, Ambrosioni E, Bertomeu V, Clement D, Erdine S, Farsang C, Gaita D, Lip G, Mallion JM, Manolis AJ, Nilsson PM, O'Brien E, Ponikowski P, Redon J, Ruschitzka F, Tamargo J, van Zwieten P, Waeber B, Williams B; Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007 Jun;25(6):1105-87. doi: 10.1097/HJH.0b013e3281fc975a. No abstract available.