Vasopressin and Vasopressin Antagonists in Heart Failure

Abstract

Despite the introduction of multiple new pharmacological agents over the past three decades in the field of heart failure (HF), overall prognosis remains poor. Hyponatremia is prevalent in HF patients and has been suggested as a contributor to poor response to standard therapy. Elevated levels of arginine vasopressin (AVP), a peptide hormone produced in the hypothalamus, play a role in development of hyponatremia, and AVP and its surrogate, copeptin, are related to changes in osmolality, hemodynamics, neuro-hormones as well as in overall outcome in HF patients. Of current pharmacological interest are the selective and non-selective vasopressin receptor antagonists (VRAs), which inhibit vasoconstriction and cardiac remodeling mediated by the V_1a receptors in smooth blood vessels, and water retention (increased urine osmolality and decreased water excretion) by increasing aquaporin-2 water channels mediated by the V₂ receptors in the renal collecting tubules. The optimal use of VRAs is yet to be determined, especially in patients with congestive HF. Although long-term effects on improvement in mortality have not been shown in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, the only long-term outcome trial to date, many short-term studies indicate beneficial aquaretic- and hemodynamic-effects of the VRAs. In contrast to loop diuretics, these new agents tend to increase urine flow and the excretion of electrolyte-free water (so-called aquaresis) in patients with HF, without substantial changes in sodium or potassium excretion. This chapter reviews the role of AVP and copeptin in HF, and the treatment potential of VRAs in HF.

Appendix: Main Study Characteristics and Results of the Vasopressin Receptor Antagonist Clinical Trials

Study	Design	Treatment	Target receptor	Patient characteristics	Effect on primary (important secondary) endpoints
Creager et al. (1986), n = 10	Controlled	iv V1a RA of 0.5 mg administered over 5 min % diuretics 24 h prior to experiment	V1A	Chronic NYHA III–IV average EF = 24 ± 10% only men	↓ SVR and ↑ CI when baseline AVP was above normal
Udelson et al. (2001), n = 142	Multicenter trial with a baseline inpatient phase, and a randomized, double-blind treatment phase	Single dose iv conivaptan (10, 20, or 40 mg) vs. placebo in a 1:1:1:1 ratio + standard therapy	V1A/V2	Chronic NYHA III–IV EF ≤ 40%	↓ PCWP, ↓ RAP and dose-dependent ↑ in urine output in the treatment group vs. placebo no difference in CI, SVR, PVR, BP, HR between the groups
The ACTIV in CHF study (Gheorghiade et al. 2004), n = 319	Multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging, phase 2 feasibility trial	Oral tolvaptan OD (30, 60, or 90 mg) vs. placebo in a 1:1:1:1 ratio up to 60 days + standard therapy	V2	Acute/chronic NYHA III–IV EF ≤ 40%	Day 1+ at discharge: non-dose-dependent ↓ BW and ↑ urine volume in the treatment group vs. placebo60-day mortality: trend toward ↓ mortality in the treatment group
The EVEREST clinical status trials (Gheorghiade et al. 2007) trial A: n = 2,048, trial B: n = 2,085	Multicenter, randomized, double-blind, placebo-controlled, phase 3	Oral tolvaptan 30 mg OD vs. placebo in a 1:1 ratio for minimum 60 days + standard therapy	V2	Acute NYHA III–IV EF ≤ 40%	At day 7/discharge: ↓ BW, ↑ Na+, ↓ dyspnea, and ↓ edema in the treatment group vs. placebo general clinical status did not differ between the groups
The EVEREST outcome trial (Konstam et al. 2007), trials A and B: n = 4,133	Multicenter, randomized, double-blind, placebo-controlled, phase 3	Oral tolvaptan 30 mg OD vs. placebo in a 1:1 ratio for minimum 60 days + standard therapy	V2	Acute NYHA III–IV EF ≤ 40%	No difference in mortality or re-hospitalization between groups KCCQ summary score not improved at outpatient week 1 sustained ↓ BW and ↑ Na+ in the treatment group
The METEOR trial (Udelson et al. 2007), n = 240	Multicenter, randomized, double-blind, placebo-controlled	Oral tolvaptan 30 mg OD vs. placebo in a 1:1 ratio for 1 year + standard therapy	V2	Chronic NYHA II–III EF ≤ 30%	No effect on LV remodeling, although small ↓ LVEDV index in the treatment group vs. placebo (no significant between group difference) favorable effect of treatment on mortality/HF hospitalization
The ECLIPSE trial (Udelson et al. 2008), n = 181	International, multicenter, randomized, placebo-controlled	Oral tolvaptan 15, 30, or 60 mg OD vs. placebo in a 1:1 ratio	V2	Acute NYHA II–III EF ≤ 30%	↓ PCWP, ↓ PAP (all treatment groups), ↓ RAP (tolvaptan 15 and 30 mg) vs. placebo dose-dependent ↑ in urine output no difference in CI, PVR, SVR between groups
Goldsmith et al. (2008), n = 170	Multicenter, double-blind, dose-ranging pilot study	iv loading dose of conivaptan 20 mg, followed by two successive 24 h continuous infusions of 40, 80, or 120 mg/day vs. placebo in a 1:1:1:1 ratio+ standard therapy	V1A/V2	Acute pulmonary congestion, respiratory symptoms NYHA III–IV mean (SD) EF = 29.5% (15.6)	↑ urine output, ↓ BW in the treatment group vs. placebo no difference in worsening HF, respiratory status at 48 hours, or electrolyte disturbances between the groups
Mao et al. (2009), n = 203	Multicenter, 4-day open-label	iv loading dose over 30 min of conivaptan 20 mg, followed by a continuous 4-day infusion of 20 or 40 mg/day	V1A/V2	CHF (n = 90) s-Na+ ≤ 130 mmol/L euvolemic- or hypervolemic-hyponatremia	Conivaptan concentrations: highest after 30 min loading dose, declined during day 1, and were maintained by the continuous infusion no difference with regard to status of volume or CHF
Udelson et al. (2011), n = 83	Multicenter, randomized, double-blind, placebo-controlled, parallel group	Oral tolvaptan 30 mg, furosemide 80 mg, or tolvaptan 30 mg + furosemide 80 mg vs. placebo in a 1:1:1:1 ratio + standard therapy	V2	Acute: signs of congestion (edema, rales) NYHA II–III EF ≤ 40%	Day 8: ↓ BW in all treatment groups, and ↑ urine volume in the two treatment groups with tolvaptan vs. placebo ↑ Na+ within the normal range, no change in K+ or BP in the group with tolvaptan
Goldsmith et al. (2011), n = 8	Randomized, cross-over study	Three separate study days separated with a 7-day washout periods: iv furosemide (<80 mg), iv loading dose of conivaptan 20 mg, followed by a continuous infusion at 1.2 mg/h for 4 h, or the combination	V1A/V2	Chronic NYHA II–III EF ≤ 23 ± 7% only men	↑ urine volume in all treatment groups and ↑ urinary Na+ excretion with furosemide therapy (combination > monotherapy) no difference in hemodynamics, neurohormonal levels, renal blood flow, or GFR
The DILIPO study (Aronson et al. 2011), n = 118	Multicenter, randomized, double-blind, placebo-controlled phase; followed by a 1-year open-label non-comparative phase	Oral satavaptan OD (25 or 50 mg) vs. placebo in a 1:1:1 ratio up to 4 days, followed by satavaptan 12.5–25 mg + fluid restriction 1–1.5 L	V2	Chronic (n = 90) NYHA III–IV s-Na+ = 115–132 mmol/L	Higher ↑ in Na+, ↓ time to response, and ↑ BW reduction in the treatment group vs. placebo similar results in the CHF subgroup the increase in Na+ was maintained long-term
Mondritzki et al. (2011), n = 6	Randomized, controlled	After iv infusion of AVP to keep its levels controlled, randomization to either conivaptan or tolvaptan, both iv 0.1 mg/kg bolus	V2 vs. V1A/V2	Mongrel dogs were paced continuously at 220 beats/min after 14 days they underwent acute testing	↑ CO and ↓ SVR with conivaptan ↓ CO and ↑ SVR with tolvaptan no difference in effect on MAP, dP/dtmax, CVP, and urine output between the groups
Ghali et al. (2012), n = 170	Multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2	Oral lixivaptan 100 mg OD vs. placebo in a 2:1 ratio for 8 weeks + standard therapy	V2	Chronic NYHA II–III EF < 40% (n = 57%) EF ≥ 40% (n = 43%)	Day 1 + weeks 1, 2, 4: ↓ BW in the treatment group vs. placebo improvement in orthopnea and dyspnea in the treatment group

1. iv intravenous, RA receptor antagonist, NYHA New York Heart Association, EF ejection fraction, SVR systemic vascular resistance, CI cardiac index, AVP arginine vasopressin, PCWP pulmonary capillary wedge pressure, PAP pulmonary artery pressure, RAP right atrial pressure, PVR pulmonary vascular resistance, BP blood pressure, HR heart rate, Na ⁺ sodium, KCCQ Kansas City Cardiomyopathy Questionnaire, LV left ventricular, LVEDV LV end-diastolic volume, HF heart failure, SD standard deviation, CHF congestive HF, K ⁺ potassium, CO cardiac output, MAP mean arterial pressure, CVP central venous pressure