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

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

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

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.

The very nature of the intervention assessed prevents any form of blinding, neither for care providers, nor for patients. However, the primary outcome is a composite outcome of events which we plan to adjudicate. As a consequence, the primary outcome will be blindly assessed.

Antihypertensive algorithm based on diuretics agents : the clinicians will adjust the drug therapy according to the antihypertensive algorithm based on diuretics agents.

Standard of care : the clinicians will adapt the antihypertensive strategy according to his own standard of care which can be pharmacological or non-pharmacological therapies.

The primary endpoint is a time to event outcome, considering the following composite endpoint: End stage kidney disease eGFR decline of at least 40% Cardiovascular events among myocardial infarction, heart failure, hospitalization and stroke All cause mortality

The primary endpoint is a time to event outcome, considering the following composite endpoint: End stage kidney disease eGFR decline of at least 40% Cardiovascular events among myocardial infarction, heart failure, hospitalization and stroke All cause mortality

The primary endpoint is a time to event outcome, considering the following composite endpoint: End stage kidney disease eGFR decline of at least 40% Cardiovascular events among myocardial infarction, heart failure, hospitalization and stroke All cause mortality

The primary endpoint is a time to event outcome, considering the following composite endpoint: End stage kidney disease eGFR decline of at least 40% Cardiovascular events among myocardial infarction, heart failure, hospitalization and stroke All cause mortality

Time to the first cardiovascular event among myocardial infarction, heart failure, hospitalization and stroke

Systolic and diastolic blood pressure at months 3 and 6 then every 6 months (home blood pressure monitoring and office blood pressure measurement),

Proportion of patients with controlled blood pressure at 2 years (PA< 135/85mmHg with home blood pressure monitoring)

Change from baseline in glomerular filtration rate estimated by CKD-EPI formula at months 3 and 6 then every 6 months

Change from baseline in proteinuria (g/d) or proteinuria /creatininuria (g/g) at months 3 and 6 then every 6 months

Inclusion Criteria: Male or female >=18 years and <80 years of age 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. Uncontrolled office BP (>140 and/or 90 mmHg) confirmed by home blood pressure monitoring (>135/85 mmHg) 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 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