Comparing the Effects of Spironolactone With Chlortalidone on LV Mass in Patients With CKD

• Status: Unknown status
• Trial end date: 2018-05-01
• Target enrollment: 0
• Participant gender: All

Summary

In stage 3 chronic kidney disease (CKD) the risk of death due to cardiovascular causes is high and greatly exceeds the risk of progression to end stage renal failure. This high cardiovascular risk is predominantly due to sudden cardiac death and heart failure, manifestations of left ventricular hypertrophy and fibrosis. Aldosterone appears to play an important role in the causation of this myocardial disease both by direct inflammatory and fibrotic myocardial effects and via increased arterial stiffness due to hypertrophy, inflammation, and fibrosis within the media of large arteries. Levels of aldosterone are high in CKD despite sodium overload and treatment with angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) drugs due to the twin phenomena of aldosterone escape and breakthrough. In a previous British Heart Foundation funded study, Birmingham investigators showed that the addition of the mineralocorticoid receptor blocker (MRB) spironolactone to background therapy with ACE inhibitors or ARBs caused reductions in the prognostically important parameters of arterial stiffness and LV mass. Because spironolactone therapy was also associated with significant falls in arterial pressure it remains possible that these effects were mediated simply by blood pressure reduction. In this multi-centre, randomised controlled study, the effects of treatment with spironolactone on LV mass and arterial stiffness in patients with stage 3 CKD on established ACE or ARB therapy will be compared to those of chlortalidone, a control anti-hypertensive agent. Early stage chronic kidney disease is highly prevalent and new, cost effective treatment strategies are required to reduce cardiovascular risk. This study is designed to provide the rationale for a larger study of morbidity and mortality with MRB therapy in early stage CKD.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University Hospital Birmingham
• Collaborators: Royal Free Hospital NHS Foundation Trust; University of Cambridge; University of Edinburgh
• Treatments: Chlorthalidone; Diuretics; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Sodium Chloride Symporter Inhibitors; Spironolactone

Criteria

Inclusion Criteria:

• Age >18 years

• Chronic kidney disease stage 2 or 3 (eGFR 30-89 ml/min/1.73m2 by Modification of Diet in Renal Disease equation). eGFR must be within the last 12 months, on at least 2 occasions, at least 90 days apart.

• Well controlled blood pressure

• Established (>6 weeks) on treatment with ACE inhibitors or ARBs

• Not pregnant or breast feeding

• Males of childbearing age will be required to use medically approved contraception during and for 6 weeks following the last dose of study treatment.

Exclusion Criteria:

• Diabetes mellitus

• Clinical evidence of hypovolaemia

• Recent (< 6 months) acute myocardial infarction or other major adverse cardiovascular event (STEMI, NSTEMI, unstable angina, coronary revascularization, stroke, transient ischaemic attack)

• Known left ventricular systolic dysfunction ( ejection fraction <50%) or severe valvular heart disease

• Active malignant disease with a life expectancy of <5 years

• Previous hyperkalaemia (K+ >6.0 mmol/l) without precipitating cause

• Serum K+ >5.0 mmol/l at entry

• Serum sodium <130 mmol/l at entry

• Atrial fibrillation on screening ECG

• Use of a thiazide or loop diuretic in the 6 weeks prior to enrolment

• Pregnant or breastfeeding

• Known alcohol or drug abuse

• Active chronic diarrhea

• Recent active gout (within 3 months)

• Acute kidney injury in previous 3 months

• Documented Addison's disease

• On treatment with fludrocortisone, co-trimoxazole and / or lithium therapy

• Combination treatment with ACE inhibitor and ARB

• Office blood pressure <115 mmHg systolic or <50 mmHg diastolic

• Office blood pressure uncontrolled and requiring urgent non trial treatment in the opinion of the investigator

• Unable to provide informed consent