Angiotensin-converting-enzyme (ACE) Inhibitors in Hemodialysis
Condition: Left Ventricular Hypertrophy; Hypertension
MeSH terms: Hypertension; Hypertrophy, Left Ventricular; Hypertrophy
Study type: Interventional
Phase: Phase 3

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.
    

Detailed description: 
      Angiotensin converting enzyme (ACE) inhibitors have the broader effect of any drug in
      cardiovascular medicine, reducing the risk of death, myocardial infarction, stroke, diabetes,
      and renal impairment.A recent meta-analysis of 33,500 patients included in six randomized
      clinical trials and a pooled analysis of the Heart Outcomes Prevention Evaluation (HOPE), the
      European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery
      Disease (EUROPA, and the Prevention of Events with Angiotensin-Converting-Enzyme Inhibition
      (PEACE) trials showed that ACE inhibitors reduce mortality and cardiovascular events also in
      subjects with coronary artery disease but preserved left ventricular function. However, all
      the above studies excluded patients with advanced renal insufficiency or end stage renal
      disease (ESRD). Thus, whether ACE inhibitors may have a specific cardioprotective effect also
      in this typology of patients is still matter of investigation. This is an issue of major
      clinical relevance since CV disease is the primary cause of morbidity and mortality in the
      ESRD population and affects as many as 50-60% of ESRD patients.The burden of CV disease in
      this population is predicted to dramatically increase over the next few years because of the
      rapidly increasing number of patients requiring renal replacement therapy and the increasing
      prevalence of ESRD patients at increased cardiovascular risk because of older age, diabetes
      and hypertension.

      Despite the excess CV risk, a consistent proportion of ESRD patients are not given ACE
      inhibitor therapy because of concern of hyperkalemia. Others, on the contrary, are treated on
      the basis of results of available trials. However, whether data in subjects without renal
      insufficiency can be generalized also to those with ESRD is unknown. This is an itchy point
      since dialysis patients might respond differently to therapies of proven benefits in non-ESRD
      patients. For instance, data from the German Diabetes and Dialysis study showed that, unlike
      in the general population, HmGCoA inhibitor therapy failed to decrease CV mortality in a
      hemodialysis population. Thus, ad hoc studies in the ESRD population are urgently needed. A
      recent trial, the Fosinopril in Dialysis (FOSIDIAL) study, tried to address this issue, but
      was clearly underpowered and results were inconclusive. However, evidence of a non
      significant trend to less cardiovascular events in the ACE inhibitor arm, suggests that ACE
      inhibitors might have a specific cardioprotective effect also in this population.

      Thus, whether ACE inhibitor therapy more effectively than non-RAS inhibitor therapy reduces
      CV morbidity in high risk patients on chronic dialysis therapy is worth investigating in an
      adequately powered trial.

      Aims

      The broad aim of the study is to evaluate whether ACE inhibitor therapy reduces CV mortality
      and morbidity in high-risk ESRD patients with arterial hypertension and/or LVH who are on
      chronic hemodialysis therapy since >6 months.

      Primary:

        -  To assess whether, at comparable BP control, ACE inhibitor as compared to non-RAS
           inhibitor therapy reduces the incidence of a combined end-point of CV death (including
           sudden cardiac death and cardiac arrest resuscitation) and myocardial infarction or
           non-fatal stroke.

      Secondary:

        -  To compare the incidence of the single components of the combined end-point, of
           myocardial or peripheral revascularizations, new onset of atrial fibrillation in one of
           its three forms (paroxysmal, persistent and permanent) or recurrence of the arrhythmia
           in patients who experienced paroxysmal or persistent atrial fibrillation previously,
           hospitalizations for chronic heart failure and thrombosis of the artero-venous fistula.

        -  To evaluate whether ACE inhibitors prevent, limit progression or achieve regression of
           LVH and ameliorate some of the components of the metabolic syndrome and whether these
           effects correlates with CV outcomes.

        -  To compare the cost/effectiveness of the two treatments.

      Safety:

        -  Serious (including disturbances of cardiac rhythm and electrical conduction possibly
           related to hyperkalemia) and non-serious adverse events.

        -  Any clinical or laboratory abnormality -such as symptomatic hypotension, cough,
           hyperkalemia (serum potassium >6 mEq/L), anemia requiring increasing doses of
           erythropoietin- possibly related to ACE inhibitor therapy.

      Design:

      This prospective, randomized, open label, blinded end point (PROBE) trial will include 266
      hypertensive ESRD patients with echocardiography evidence of LVH who are on chronic
      hemodialysis since >6 months. After 1 month wash-out period from previous RAS inhibitor
      therapy and stratification for diabetes YES/NO, they will have a baseline evaluation of main
      clinical and laboratory parameters and will be randomized to 2-year treatment with an ACE
      inhibitor or a BP lowering regimen not including RAS inhibitors. 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.
    

Intervention name(s): ACE inhibitor Ramipril; non-RAS inhibitor antihypertensive therapy
Intervention type(s): Drug; Drug
Intervention description(s): The ACE inhibitor (Ramipril) will be started at 1.25 mg/day and will be up-titrated to 2.5 mg/day, to 5 mg/day, and then to 10 mg/day according to BP control and tolerability.; Blood Pressure lowering regimen not including RAS inhibitors
Intervention MeSH terms: Ramipril; Antihypertensive Agents; Angiotensin-Converting Enzyme Inhibitors
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hemodialysis