Intensification of Blood Pressure Lowering Therapeutics Based on Diuretics Versus Usual Management for Uncontrolled Hypertension IN Patients With Moderate to Severe Chronic Kidney Disease

Official title

Intensification of Blood Pressure Lowering Therapeutics Based on Diuretics Versus Usual Management for Uncontrolled Hypertension IN Patients With Moderate to Severe Chronic Kidney Disease: an Open Label, a Cluster Randomized Controlled, Phase 3 Trial

Overview

Chronic kidney disease (CKD) is a major public health issue worldwide. Hypertension is the first risk factor in patients with CKD for mortality, cardiovascular disease and end-stage renal disease. It's now well established that lowering blood pressure (BP) reduces renal and cardiovascular complications in this high-risk population. In the general population, in addition to lifestyle interventions, the strategy to initiate and escalate a BP-lowering drug treatment is well described. The drug therapies recommended to achieve optimal BP control in the general population are the following: blockers of the renin-angiotensin system (angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB)), diuretics (thiazides and thiazide-like diuretics), and calcium channel blockers. For patients with CKD, the guidelines advise to start the BP-lowering agent with ACEi or ARB, but then, there is no strong evidence to support the preferential use of any particular agent in controlling BP and the results of clinical trials are discordant. In the NephroTest cohort, a French cohort of patients with CKD stage 1 to 5, among 2015 patients, 1782 had hypertension, only 54% had a diuretic and 44% had uncontrolled hypertension. In this cohort, extracellular fluid (ECF) overload was an independent determinant of hypertension, uncontrolled hypertension and apparent treatment resistant hypertension. In the same cohort, ECF overload was independently associated with end-stage kidney disease and death. Our hypothesis is that patients with CKD and uncontrolled hypertension are fluid overloaded and that the second line of treatment after an ACEi or an ARB should be a diuretic. We hypothesize that a specific algorithm to lower BP in patients with moderate to severe CKD based on diuretics will be more effective in term of cardiovascular event, mortality and evolution to end-stage kidney disease as compared to standard of care.

Interventions

• Drug Antihypertensive algorithm
  Antihypertensive algorithm based on diuretics agents
• Drug Standard of care
  standard of care management for antihypertensive therapy intensification

Primary outcome measures

• End stage kidney disease [Time frame: Up to 36 months]
• eGFR decline of at least 40% [Time frame: Up to 36 months]
• Cardiovascular events [Time frame: Up to 36 months]
• All cause mortality [Time frame: Up to 36 months]

Secondary outcome measures (10)

• Time to end-stage kidney disease [Time frame: Up to 36 months]
• Time to eGFR decrease of at leat 40% [Time frame: Up to 36 months]
• Time to the first cardiovascular event among myocardial infarction, heart failure, hospitalization and stroke [Time frame: Up to 36 months]
• All-cause mortality [Time frame: Up to 36 months]
• Change from baseline in blood pressure [Time frame: From baseline and up to 36 months]
• Proportion of patients with controlled blood pressure [Time frame: 24 months]
• Change from baseline in glomerular filtration rate [Time frame: From baseline and up to 36 months]
• Change from baseline in proteinuria (g/d) or proteinuria /creatinuria (g/g) [Time frame: From baseline and up to 36 months]
• Proportion of patients who used at least one diuretic [Time frame: Up to 36 months]
• Change from baseline in quality of life [Time frame: From baseline and up to 36 months]

Eligibility criteria

Inclusion criteria

• Male or female >=18 years with a clinical frailty score ≤5 for patient aged over 80
• Advanced or moderate chronic kidney disease (eGFR 15 to 44.9 mL/min/1.73m² using CKD-EPI formula)
• Arterial hypertension treated with at least one blood pressure lowering drug therapy among blockers of the renin-angiotensin system (ACEi or ARB), at the maximal posology tolerated by the patients stable since at least one month. Other blood pressure lowering drug therapies are tolerated in combination with or in the event of intolerance to ACE inhibitors or ARBs.
• Uncontrolled office BP
• Uncontrolled office BP (>140 and/or 90 mmHg) confirmed by home blood pressure monitoring (>135 and/or 85 mmHg) or Day-time Ambulatory Blood Pressure Monitoring
• Participant covered by or entitled to social security
• Written informed consent obtained from the participant

Exclusion criteria

• Patient following any measures of legal presentation
• Pregnant or breastfeeding woman
• woman of childbearing without a highly effective contraceptive measure (combined or progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device or intrauterine hormone-releasing system)
• Clinical signs of hypovolemia
• Symptomatic orthostatic hypotension
• Hyponatremia (<130 mmol/L)
• Dyskalemia (<3,5 mmol/L or >5,5 mmol/L)
• Major adverse cardiovascular event during the last three months: myocardial infarction, heart failure hospitalization, stroke
• Current medical history of cancer requiring chemotherapy
• Solid organ transplantation
• Two or more diuretic agents (loop diuretic, thiazides and thiazide-like diuretics)
• Mineralocorticoid receptor antagonists
• Autosomal dominant polycystic kidney disease treated with Tolvaptan
• Contraindication to diuretics involved in the algorithm
• Severe heart failure (NYHA III\_IV)
• Cirrhosis Child B-C

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 40 centers

• Department of Nephrology, University Hospital of Angers — Angers
• Department of Nephrology, University Hospital of Bordeaux — Bordeaux
• AUB Santé foundation, Brest — Brest
• Department of Nephrology, University Hospital of Brest — Brest
• Department of Nephrology, Hospital of Chalon-sur-Saône — Chalon-sur-Saône
• Department of Nephrology, Hospital of Chartres — Chartres
• Department of Nephrology, University Hospital of Clermont-Ferrand — Clermont-Ferrand
• Department of Nephrology, Hospital of Colmar — Colmar
• … and 32 more centers

Identifiers

NCT: NCT05732727 · DR210320 · 2022-501494-39-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗