Angiotensin-converting-enzyme (ACE) Inhibitors in Hemodialysis

• Status: Completed
• Trial end date: 2016-04-01
• Target enrollment: 0
• Participant gender: All

Summary

Background: Angiotensin-converting-enzyme (ACE) inhibitors have a specific cardioprotective effect and, compared to treatment not directly interfering with the renin-angiotensin-system (RAS), significantly reduce cardiovascular (CV) mortality and morbidity in subjects with normal renal function.

Despite CV events are the leading cause of death in these patients, no adequately powered trial so far evaluated the specific cardioprotective effect of ACE inhibitors in this population.

Objectives: This prospective, randomized, open label, blinded end point (PROBE) trial is primarily aimed at evaluating whether, at comparable blood pressure (BP) control, ACE inhibitor as compared to non-RAS inhibitor therapy significantly reduces the incidence of a composite end point of CV death (including sudden death) and non-fatal myocardial infarction or stroke in 266 patients with arterial hypertension (pre-dialysis systolic/diastolic BP >140/90 mmHg or post-dialysis systolic/diastolic BP >130/80 mmHg or antihypertensive therapy) and/or echocardiography evidence of LVH (cardiac mass index >130 g/m2 for men and 100 g/m2 for women) who are on dialysis therapy since at least six months. Secondarily, the study will compare the incidence of single components of the primary outcome, new onset paroxysmal or persistent atrial fibrillation, thrombosis of the artero-venous fistula, new onset, progression or regression of LVH, changes in components of the metabolic syndrome, the safety profile of the two treatment regimens and their cost/effectiveness.

Methods: After 1 month wash-out period from previous RAS inhibitor therapy and a baseline evaluation of main clinical and laboratory parameters, patients will be randomized on a 1:1 basis to 2-year treatment with an ACE inhibitor or a BP lowering regiment not including RAS inhibitors. A balanced distribution according to centre, number of dialysis sessions per week (2 or 3), presence of diabetes (YES/NO), arterial hypertension (YES/NO), LVH (YES/NO) will be achieved by the minimization method. Treatment will be adjusted to achieve and maintain a target BP <140/90 mmHg (pre-dialysis) and a target BP <130/80 mmHg (post-dialysis) in both groups.

Expected results: ACE inhibitor compared to non-RAS inhibitor therapy is expected to reduce more effectively fatal and non-fatal CV events, prevent or limit progression or induce regression of LVH, improve some components of the metabolic syndrome, and reduce treatment costs for cardiovascular complications. These findings might help achieving more effective cardioprotection in people on chronic dialysis at lower costs.

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Mario Negri Institute for Pharmacological Research
• Collaborator: Agenzia Italiana del Farmaco
• Treatments: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Ramipril

Criteria

Inclusion criteria:

• Men and women >18 years of age who are on chronic renal replacement treatment since at least 6 months with two or three haemodialysis sessions per week.

• Hypertension (pre-dialysis systolic and/or diastolic BP >140/90 mmHg or post-dialysis systolic and/or diastolic BP >130/80 mmHg or ongoing antihypertensive therapy).

and/or

• LVH defined by a cardiac mass index >130 g/m2 for men and 100 g/m2 for women (17) within three months of enrolment.

• Written informed consent.

Exclusion criteria:

• Specific indication (such as heart failure) or contraindication (such as hypersensitivity) to ACE inhibitor therapy.

• Any concomitant medication with ACE inhibitors and angiotensin II receptor antagonists

• Hyperkalemia (serum potassium >6 mEq/L) despite optimal control of metabolic acidosis and blood glucose (in diabetics) in patient with less then three dialysis sessions per week.

• Symptomatic chronic or intradialytic hypotension.

• Arrhythmias that in the Investigator judgement might be worsened by hyperkalemia (such as sinus bradycardia, delayed atrio-ventricular conduction, atrio-ventricular blocks).

• CV events (stroke, acute myocardial infarction or other acute coronary syndromes) over the last three months.

• Uncontrolled hyper- or hypo-thyroidism.

• Active systemic disease, malignancies and any clinical condition associated with a life-expectancy of less than 2 years.

• Drug or alcohol abuse, psychiatric disorders and inability to understand the potential risks or benefits of the study.

• Pregnancy, lactation or child bearing potential and ineffective contraception.