Angiotensin-converting-enzyme (ACE) Inhibitors in Hemodialysis (ARCADIA)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Agenzia Italiana del Farmaco
Information provided by (Responsible Party):
Mario Negri Institute for Pharmacological Research
ClinicalTrials.gov Identifier:
NCT00985322
First received: September 25, 2009
Last updated: March 6, 2014
Last verified: March 2014
  Purpose

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 624 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.


Condition Intervention Phase
Left Ventricular Hypertrophy
Hypertension
Drug: ACE inhibitor Ramipril
Drug: non-RAS inhibitor antihypertensive therapy
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Prospective, Randomized, Open Label, Blinded End-point (Probe) Trial to Evaluate Whether, at Comparable Blood Pressure Control, ACE Inhibitor Therapy More Effectively Than Non RAS Inhibitor Therapy Reduces CArdiovascular Morbidity and Mortality in Chronic DIAlysis Patients With Left Ventricular Hypertrophy and/or Arterial Hypertension (ARCADIA Study)

Resource links provided by NLM:


Further study details as provided by Mario Negri Institute for Pharmacological Research:

Primary Outcome Measures:
  • The main outcome variable will be a combined end-point of cardiovascular death (including sudden death and cardiac arrest resuscitation) and myocardial infarction or non-fatal stroke. [ Time Frame: Baseline, 1st and 2nd year ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Single components of combined endpoint,myocardial or peripheral revascularizations,new onset paroxysmal,persistent or permanent or recurrence of atrial fibrillation,hospitalizations for chronic heart failure,and thrombosis of artero-venous fistula [ Time Frame: Baseline, 1st and 2nd year ] [ Designated as safety issue: Yes ]

Enrollment: 269
Study Start Date: May 2009
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ACE inhibitor Ramipril Drug: ACE inhibitor Ramipril
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.
Active Comparator: non-RAS inhibitor antihypertensive therapy Drug: non-RAS inhibitor antihypertensive therapy
Blood Pressure lowering regimen not including RAS inhibitors

  Hide Detailed Description

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 624 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.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00985322

Locations
Italy
Policlinico San Pietro
Ponte San Pietro, Bergamo, Italy
Ospedale "Treviglio-Caravaggio"
Treviglio, Bergamo, Italy
Hospital of Montichiari
Montichiari, Brescia, Italy
Presidio Ospedaliero Acireale
Acireale, Catania, Italy
Hospital "Morgagni-Pierantoni"
Forlì, Forlì Cesena, Italy
A.O. Desio e Vimercate
Desio, MB, Italy
Ospedale "Caduti Bollatesi"
Bollate, Milano, Italy
Hospital of Cernusco sul Naviglio
Cernusco sul Naviglio, Milano, Italy
Hospital "Bassini"
Cinisello Balsamo, Milano, Italy
A.O. Ospedale Civile di Legnano
Legnano, Milano, Italy
A.O. della Provincia di Lodi
Lodi, Milano, Italy
Presidio Ospedaliero di Magenta
Magenta, Milano, Italy
IRCCS "Humanitas"
Rozzano, Milano, Italy
IRCCS Multimedia
Sesto San Giovanni, Milano, Italy
Fondazione San Raffaele Monte Tabor
Milan, MI, Italy
Ospedale San Giovanni di Dio
Agrigento, Italy
Hospital "Ospedali Riuniti "
Bergamo, Italy
Cliniche Humanitas Gavazzeni
Bergamo, Italy
Hospital "Policlinico S.Orsola-Malpighi"
Bologna, Italy
A.O. Giuseppe Brotzu
Cagliari, Italy
ASL 8 - S.C. Territoriale di Nefrologia e Dialisi
Cagliari, Italy
A.O. S. Croce e Carle, Cuneo
Cuneo, Italy
Hospital "San Paolo"
Milano, Italy
Hospital "San Gerardo"
Monza, Italy
Hospital "Azienda Ospedaliera Universitaria Di Parma"
Parma, Italy
Arcispedale Santa Maria Nuova
Reggio Emilia, Italy
Hospital "Degli Infermi"
Rimini, Italy
A.O. Umberto I
Siracusa, Italy
P.O. G. Mazzini
Teramo, Italy
Sponsors and Collaborators
Mario Negri Institute for Pharmacological Research
Agenzia Italiana del Farmaco
Investigators
Study Director: Piero Ruggenenti, MD Mario Negri Institute for Pharmacological Research
  More Information

No publications provided

Responsible Party: Mario Negri Institute for Pharmacological Research
ClinicalTrials.gov Identifier: NCT00985322     History of Changes
Other Study ID Numbers: ARCADIA, 2008-003529-17
Study First Received: September 25, 2009
Last Updated: March 6, 2014
Health Authority: Italy: Ministry of Health

Keywords provided by Mario Negri Institute for Pharmacological Research:
Hemodialysis

Additional relevant MeSH terms:
Hypertension
Hypertrophy
Hypertrophy, Left Ventricular
Vascular Diseases
Cardiovascular Diseases
Pathological Conditions, Anatomical
Cardiomegaly
Heart Diseases
Ramipril
Angiotensin-Converting Enzyme Inhibitors
Antihypertensive Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Cardiovascular Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 15, 2014