Diuretic and Renal Effects of Vaprisol When Administered Along With Furosemide and Nesiritide Continuous Infusion

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00806910
Recruitment Status : Withdrawn (Sponsor support withdrawn)
First Posted : December 11, 2008
Last Update Posted : June 23, 2011
Astellas Pharma Inc
Information provided by:
Albert Einstein Healthcare Network

Brief Summary:
Heart Failure is a growing and challenging public health concern in the United States. Heart failure commonly manifests as a syndrome of salt and water retention. Arginine vasopressin is a peptide hormone that is intimately involved in salt and water homeostasis. AVP is released into the circulation in response low blood volume and hypernatraemia. Despite fluid overload, vasopressin levels are often inappropriately elevated in patients with heart failure and LV dysfunction. Data suggest that vasopressin may also contribute to the deleterious circulatory response in patients with heart failure and play a role in the development and progression of the disease process. In their study, Udelson et al. showed that vasopressin receptor antagonism with Conivaptan resulted in significant diuresis with stable hemodynamics in advanced heart failure patients. Currently Intravenous diuretics and vasodilators are the standard of care in treating patients with acute decompensated heart failure. We will be studying the renal and diuretic effects of add on therapy with intravenous Conivaptan in patients receiving intravenous Nesiritide and intravenous diuretics.

Condition or disease Intervention/treatment Phase
Heart Failure Drug: Conivaptan Other: Placebo Phase 4

Detailed Description:

Heart failure effects 5 to 6 million Americans and is increasing in prevalence. There are about 550, 000 new cases of heart failure every year and about 3 million admissions for acute decompensated heart failure every year. The total cost of heat failure on the health systems is upwards of 35 billion dollars per year. Despite advances in medical care, the hospital readmission rate is 20% at one month and 50% at six months. This prevailing situation mandates further exploration of novel therapeutic targets to treat this complex disease.

Vasopressin levels are often elevated in patients with heart failure and LV dysfunction which is paradoxical and inappropriate. It has been hypothesized that high levels of circulating vasopressin may play an important role not only in the pathophysiology of the heart failure syndrome but also contribute to its disease progression.

Studies have shown that Conivaptan, a Vasopressin antagonist results in favorable changes in hemodynamics and urine output without affecting blood pressure or heart rate. No consensus has been reached for Conivaptan to be used as a sole agent in Acute Decompensated Heart Failure (ADHF) patients and IV loop diuretics and/or vasodilators such as Nesiritide are used as the prime treatment for vascular congestion. This prevailing situation brings the questions whether, Conivaptan can be used as an adjunct to IV Furosemide and/or Nesiritide presenting with ADHF.We intend to investigate this question in a cohort of heart failure patients with hyponatremia.

This study will enroll 60 patients ( who meets all the inclusion criteria and none of the exclusion criteria), admitted to the Albert Einstein Medical Center with the diagnosis of Acute Decompensated Heart Failure (New York Heart Association class 3 and 4). The study population will be divided into 2 groups; a treatment group and a placebo group as described below. Each group will be comprised of 30 patients.

The treatment group will be treated with Nesiritide infusion, intravenous Furosemide (either continuous infusion or bolus injection- total dose of Furosemide received at the end of the study will be calculated) and IV Vaprisol. The placebo group will be given Nesiritide infusion and intravenous Furosemide(either continuous infusion or bolus injection) and placebo. Treatment will be continued in both groups for 24-36 hours.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Evaluation of the Diuretic and Renal Effects of Vaprisol When Administered Along With Furosemide and Nesiritide Continuous Infusion
Study Start Date : October 2008
Actual Primary Completion Date : February 2010
Actual Study Completion Date : February 2010

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arm Intervention/treatment
Active Comparator: Treatment
Subjects will be treated with Intravenous Vaprisol along with Nesiritide infusion and intravenous Furosemide (either continuous infusion or bolus injections - total dose of Furosemide received will be calculated at the end of the study).
Drug: Conivaptan
IV Vaprisol initially at 20 mg IV injection over 30 minutes, followed by a 20 mg IV infusion over the next 24 hours (i.e. 20 mg bolus, 20 mg continuous infusion approximately 24 hrs).
Other Name: Vaprisol

Placebo Comparator: Placebo
Subjects will be given Placebo (at the same rate of Vaprisol given in the treatment arm) along with Nesiritide infusion and intravenous Furosemide (either continuous infusion or bolus injections - total dose of Furosemide received will be calculated at the end of the study).
Other: Placebo
Placebo (will be given at the same rate of Vaprisol given in the treatment arm)
Other Name: Saline

Primary Outcome Measures :
  1. Degree of diuresis as measured by weight change and intake and output measurement [ Time Frame: Post infusion, Pre discharge and at 30 day Post discharge ]

Secondary Outcome Measures :
  1. Length of stay (LOS) in hospital [ Time Frame: Concurrent ]
  2. Clinical status based on NYHA criteria [ Time Frame: Pre-discharge and 30-day post-discharge follow up ]
  3. Serum electrolytes [ Time Frame: Pre and Post infusion ]
  4. BUN and Serum Creatinine concentration [ Time Frame: Post infusion, Pre discharge and at 30 day Post discharge ]
  5. Number of readmissions due to ADHF [ Time Frame: Within 30-day post-discharge follow up ]
  6. Dyspnea assessment by Visual Analog Scale score [ Time Frame: Post infusion, Pre discharge and at 30 day Post discharge ]
  7. Subjective feeling based on Minnesota - Living with Heart Failure Questionnaire [ Time Frame: Pre-discharge and 30-day post-discharge follow up ]

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients over the age of 18 and able to consent
  • LVEF ≤40% (as measured within last 6 months before entering into the study)
  • Patients with Acute Decompensated Heart Failure (ADHF) (NYHA class 3 & 4)
  • Patients with estimated GFR >40ml/min as calculated by Cockcroft-Gault or MDRD formula
  • Serum Sodium level <135 meq/L
  • Ability to understand and willing to sign informed consent
  • Willingness to follow-up in the clinic as outpatient

Exclusion Criteria:

  • Patients with Acute Coronary Syndrome (ACS: Unstable angina, NSTEMI or STEMI)
  • Patients on pressors (including Vasopressin analogs) for hemodynamic stability
  • Supine systolic blood pressure <100 mm Hg
  • Hypersensitivity to Conivaptan
  • Concomitant use of medications that affects hepatic drug metabolism (e.g. Ketoconazole, Itraconazole, Ritonavir, Indinavir, Clarithromycin etc.)
  • Significant liver dysfunction (ALT & AST more than twice the upper limit of normal)
  • Uncontrolled bradyarrhythmias or tachyarrhythmias
  • Pacemaker or defibrillator implantation or other cardiac surgery <60 days
  • Severe obstructive pulmonary disease
  • Significant uncorrected valvular or congenital heart disease
  • Obstructive cardiomyopathy
  • Significant renal impairment (defined as a serum creatinine >2.5 mg/dL or creatinine clearance <40 ml/min).
  • Radiocontrast infusion within <7 days
  • Pregnant or lactating female subject
  • Untreated severe hyperthyroidism, hypothyroidism or adrenal insufficiency
  • Expected requirement for emergent treatment of hypernatremia during the course of the study
  • Known urinary outflow obstruction, unless subject is, or can be catheterized during the study
  • Serum albumin < 1.5 gm/dl documented any time during any time during seven days prior to study drug administration
  • Any concurrent illness, which in opinion of the investigator, may interfere with treatment or evaluation of safety.
  • White blood cell count (WBC) count < 3000 /mL documented any time during seven days prior to study drug administration or anticipated drop in WBC count <3000/mL during the period of study due to chemotherapy.
  • Participation in another clinical trial of an investigational drug (including placebo) or device within 30 days of screening for entry into the present study
  • Subject has moderate ascites on physical examination secondary to hepatic dysfunction (ascites primarily related to cardiac dysfunction will be allowed as long as subject does not have cardiac cirrhosis).
  • Subject has moderate to severe hepatic impairment as evidenced by Child-Pugh B or C criteria.
  • Subject has a history of hepatic encephalopathy, hematemesis or melena.
  • Subjects with altered mental status due to severe hyponatremia.
  • Patient belonging to a vulnerable population such as institutionalized person, prisoners and persons with decisional incapacity or dementia.
  • Patients on medications which are known to cause drug interactions such as Nicardipine, lovastatin, Ritonovir, Doxorubicin Etc

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00806910

Sponsors and Collaborators
Albert Einstein Healthcare Network
Astellas Pharma Inc
Principal Investigator: Darshak H Karia, MD Albert Einstein Medical Center

Responsible Party: Darshak H. Karia, MD. Director, Heart Failure Services, Albert Einstein Heart and Vascular, Albert Einstein Medical Center Identifier: NCT00806910     History of Changes
Other Study ID Numbers: HN-4040
First Posted: December 11, 2008    Key Record Dates
Last Update Posted: June 23, 2011
Last Verified: June 2011

Keywords provided by Albert Einstein Healthcare Network:
Heart Failure

Additional relevant MeSH terms:
Heart Failure
Heart Diseases
Cardiovascular Diseases
Natriuretic Peptide, Brain
Natriuretic Agents
Physiological Effects of Drugs
Sodium Potassium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Antidiuretic Hormone Receptor Antagonists