Effects on Exercise Hemodynamics of Vasopressin Blockade by Conivaptan Infusion in Heart Failure Patients

Effects on Exercise Hemodynamics of Vasopressin Blockade by Conivaptan Infusion in Heart Failure Patients

The purpose of the present study is to evaluate the effects of a blockade of the vasopressin system and central hemodynamic system in heart failure (HF) patients during physical exercise. The significance of the vasopressin system during physical exercise is unclear. If vasopressin is a significant regulator of exercise hemodynamics in HF, strategies to intervene against activation of the V1A-receptor might be expected to improve HF symptoms and possibly outcome.

The potential effects of the central hemodynamic system will be evaluated with a Swan-Ganz catheter. Echocardiography will be performed at rest and during submaximal working capacity before and during the infusion of a vasopressin receptor antagonist (conivaptan) or placebo. Cardiac output will be measured by thermodilution. The exercise test will be performed at 50 % of VO2 max and hemodynamic and echocardiographic measurements will be collected. The exercise test will be performed on a supine multistage bicycle.

Inclusion Criteria:

• Age > 18 years
• Left ventricular ejection fraction (LVEF) < 45 % on the baseline echocardiography.
• Treatment with beta-blockers and angiotensin-converting-enzyme (ACE) inhibitors for at least 1 month as tolerated
• New York Heart Association (NYHA) Functional Class II-III
• Given informed consent
• Women, who have not yet entered menopause (defined as no menstrual bleeding in the last 12 months), will provide a negative urine HCG before entering the study

Exclusion Criteria:

• Signs of symptomatic or ongoing myocardial ischemia
• Known non-revascularized coronary disease
• Presence of hypovolemic hyponatremia (P-Na+ <130 mmol/l and clinical signs of volume depletion or dehydration as judged by investigator).
• Hypernatraemia (P-Na+) > 145 mmol/L
• Chronic obstructive pulmonary disease (FEV1/FVC < 70 % and/or 30 % > FEV1 < 50 %)
• Supine systolic blood pressure < 85 mmHg
• Significant orthostatic hypotension
• Standing blood pressure < 80 mmHg or a blood pressure drop > 20 mmHg when changing from a supine to a standing position
• Uncontrolled hypertension evaluated by the investigator
• Uncontrolled cardiac arrhythmias evaluated by the investigator
• Untreated serious hypothyroidism
• Adrenal insufficiency
• Poor echocardiographic window
• Inability to perform exercise testing
• Permanent atrial fibrillation or atrial fluttering
• Planned coronary by-pass surgery
• Moderate hepatic impairment (ALAT/ASAT > 3 UNL)
• Presence of other diseases affecting treatment with conivaptan or the evaluation of safety as evaluated by the investigator
• Severely decreased kidney function (eGFR < 20 mL/min)
• Serum K+< 3.5 or > 5.5 mmol/L
• Known conivaptan intolerability
• Corn allergy
• Dextrose Allergy
• Treatment with potent CYP3A-inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir)
• Treatment with arginine vasopressin, oxytocin, desmopressin and other medications for the treatment of hyponatremia (lithium salts, urea and demeclocycline)
• Warfarin treatment
• Presence of infection or active bleeding