Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00985322 |
| Other study ID # |
ARCADIA |
| Secondary ID |
2008-003529-17 |
| Status |
Completed |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
May 2009 |
| Est. completion date |
April 2016 |
Study information
| Verified date |
January 2021 |
| Source |
Mario Negri Institute for Pharmacological Research |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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.
