Cardiorenal Syndrome (CRS)
Conditions
Keywords
Chronic heart failure (CHF), cardiac and renal dysfunction
Brief summary
To advance our understanding of the mechanisms of human cardiorenal syndrome with emphasis upon the interaction of diuretic therapy and the renal-angiotensin-aldosterone -system and cGMP pathway. The belief is that the chronic AT1 receptor blockade in subjects with compensated CHF and renal dysfunction will improve renal function with increased sodium excretion, glomerular filtration rate and effective renal plasma flow and renal function reserve as compared to the response of placebo-treated subjects.
Detailed description
IRB # 09-003284, Specific Aims 2: Define in humans with compensated CHF and renal dysfunction, the modulating action of chronic AT1 receptor blockade in addition to ACE inhibition on cardiorenal and humoral function, involving 12 weeks of study drug (Candesartan or placebo) starting at 4 mg daily and doubling every 2 weeks to 16 mg, if tolerated. Safety labs are performed one week after each dose increase (end of weeks 1, 3 and 5), and in week 10 of the study. Participants are monitoring their blood pressure weekly, and are aware to watch for symptoms of hypotension (lightheadedness, dizziness, blurred vision). Renal clearance testing and ECHO are performed at the start and end of the 12 weeks of study medication in the 5-Domitilla Clinical Research Unit.
Interventions
DRUGCandesartan
4 mg once a day up to 13 day. dose will be doubled every 14-18 days as tolerated to a goal of 16 mg a day or highest dose tolerated
DRUGPlacebo
4 mg once a day up to 13 day. dose will be doubled every 14-18 days as tolerated to a goal of 16 mg a day or highest dose tolerated
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Left ventricular ejection fraction of equal or less than 40% assessed by echocardiography, nuclear scan, MRI or left ventriculogram within the past 48 months. * Stable New York Heart Association (NYHA) class II and III symptoms as defined by: no change in NYHA symptoms over the past 3 months, on stable doses of ACE inhibitor, beta blocker, digoxin and furosemide over the last 4 weeks and no episode of decompensated CHF over the past 6 months. * Calculated creatinine clearance of equal or less than 80 ml/min and greater than 20 ml/min, using the MDRD formula assessed within the past 48 months and a confirmatory calculated creatinine clearance equal or less than 80 ml/min and greater than 20 ml/min at the time of enrollment. Subjects who are already taking AT1 receptor blocker will be excluded. Aldosterone antagonist, antiarrhythmic medications and other vasodilators will be allowed; however, all medications must be at stable doses 4 weeks prior to enrollment. Subjects taking nonsteroidal anti-inflammatory drugs (NSAIDs) except aspirin will not be able to increase their medication dose for the duration of the study. Subjects will be excluded if they have had a prior diagnosis of intrinsic renal disease, including renal artery stenosis of \> 50%, or if they meet any one of the
Exclusion criteria
listed below.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glomerular Filtration Rate | baseline to 3 months | Glomerular Filtration Rate estimates how much blood passes through the glomeruli each minute. Glomeruli are the tiny filters in the kidneys that filter waste from the blood. Measured as ml/min/1.73 m2 |
| Change in Urinary Sodium Excretion | baseline to 3 months | Urinary sodium excretion correlates with elevated blood pressure in subjects at low cardiovascular risk. The body continually monitors blood volume and sodium concentration. When either becomes too high, sensors in the heart, blood vessels, and kidneys detect the increases and stimulate the kidneys to increase sodium excretion, thus returning blood volume to normal. Measured as mEq/min |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Candesartan Subjects received 4 mg once a day up to 13 day. Dose was doubled every 14-18 days as tolerated to a goal of 16 mg a day or highest dose tolerated. | 16 |
| Placebo Subjects received 4 mg once a day up to 13 day. Dose was doubled every 14-18 days as tolerated to a goal of 16 mg a day or highest dose tolerated | 17 |
| Total | 33 |
Baseline characteristics
| Characteristic | Candesartan | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 68.5 years STANDARD_DEVIATION 10.4 | 68.9 years STANDARD_DEVIATION 12.3 | 69.3 years STANDARD_DEVIATION 14.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 16 Participants | 33 Participants | 17 Participants |
| Region of Enrollment United States | 16 participants | 33 participants | 17 participants |
| Sex: Female, Male Female | 2 Participants | 6 Participants | 4 Participants |
| Sex: Female, Male Male | 14 Participants | 27 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 17 |
| other Total, other adverse events | 5 / 16 | 5 / 17 |
| serious Total, serious adverse events | 0 / 16 | 0 / 17 |
Outcome results
Primary
Change in Glomerular Filtration Rate
Glomerular Filtration Rate estimates how much blood passes through the glomeruli each minute. Glomeruli are the tiny filters in the kidneys that filter waste from the blood. Measured as ml/min/1.73 m2
Time frame: baseline to 3 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Candesartan | Change in Glomerular Filtration Rate | -5 ml/min/1.73 m2 |
| Placebo | Change in Glomerular Filtration Rate | 1.00 ml/min/1.73 m2 |
p-value: 0.26t-test, 2 sided
Primary
Change in Urinary Sodium Excretion
Urinary sodium excretion correlates with elevated blood pressure in subjects at low cardiovascular risk. The body continually monitors blood volume and sodium concentration. When either becomes too high, sensors in the heart, blood vessels, and kidneys detect the increases and stimulate the kidneys to increase sodium excretion, thus returning blood volume to normal. Measured as mEq/min
Time frame: baseline to 3 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Candesartan | Change in Urinary Sodium Excretion | -8.50 mEq/min |
| Placebo | Change in Urinary Sodium Excretion | 10.00 mEq/min |
p-value: 0.67t-test, 2 sided