Efficacy and Safety of Vasopressin Receptor Antagonists for Euvolemic or Hypervolemic Hyponatremia: A Meta-Analysis

Xiangyun Zhang, Mingyi Zhao, Wei Du, Dongni Zu, Yingwei Sun, Rongwu Xiang, Jingyu Yang, Xiangyun Zhang, Mingyi Zhao, Wei Du, Dongni Zu, Yingwei Sun, Rongwu Xiang, Jingyu Yang

Abstract

Hyponatremia, defined as a nonartifactual serum sodium level <135 mmol/L, is the most common fluid and electrolyte abnormality in clinical practice. Traditional managements (fluid restriction, hypertonic saline and loop diuretics, etc.) are difficult to maintain or ineffective. Recently, vasopressin receptor antagonists (VRAs) have shown promise for the treatment of hyponatremia. We aimed to conduct a meta-analysis to evaluate the efficacy and safety of VRAs in patients with euvolemic or hypervolemic hyponatremia. We searched Pubmed, Cochrane Library, Web of Science and Springer, etc. (latest search on June 4, 2015) for English publications with randomized controlled trials. Two authors independently screened the citations and extracted data. We calculated pooled relative risk (RR), risk difference (RD), weighted mean difference (WMD) or standard mean difference (SMD), and 95% confidence intervals (CIs) by using random and fixed effect models. We collected data from 18 trials involving 1806 patients. Both random and fixed effect meta-analyses showed that VRAs significantly increased the net change of serum sodium concentration (WMD(random) = 4.89 mEq/L, 95%CIs = 4.35-5.43 and WMD(fixed) = 4.70 mEq/L, 95%CIs = 4.45-4.95), response rate (RR(random )= 2.77, 95%CIs = 2.29-3.36 and RR(fixed) = 2.95, 95%CIs = 2.56-3.41), and 24-hour urine output (SMD(random) = 0.82, 95%CIs = 0.65-1.00 and SMD(fixed) = 0.79, 95%CIs = 0.66-0.93) compared to placebo. Furthermore, VRAs significantly decreased body weight (WMD(random) = -0.87 kg, 95%CIs = -1.24 to -0.49 and WMD(fixed) = -0.91 kg, 95%CIs = -1.22 to -0.59). In terms of safety, rates of drug-related adverse events (AEs), rapid sodium level correction, constipation, dry mouth, thirst, and phlebitis in the VRA-treated group were greater than those in control group. However, there was no difference in the total number of AEs, discontinuations due to AEs, serious AEs, death, headache, hypotension, nausea, anemia, hypernatremia, urinary tract infection, renal failure, pyrexia, upper gastrointestinal bleeding, diarrhea, vomiting, peripheral edema, and dizziness between the 2 groups. Random effect meta-analyses showed that post treatment urine osmolality, supine systolic blood pressure, and diastolic blood pressure were lowered (WMD(random) = -233.07 mOsmol/kg, 95%CIs = -298.20-147.94; WMD(random) = -6.11 mmHg, 95%CIs = -9.810 to -2.41; WMD(random )= -2.59 mmHg, 95%CIs = -4.06 to -1.11, respectively), but serum osmolality was increased (WMD(random) = 9.29 mOsmol/kg, 95%CIs = 5.56-13.03). There was no significant change from baseline in serum potassium concentration between the 2 groups (WMD(fixed) = 0.00 mmHg, 95%CIs = -0.07-0.06). VRAs are relatively effective and safe for the treatment of hypervolemic and euvolemic hyponatremia.

Conflict of interest statement

The authors have no conflicts of interest to disclose.

Figures

FIGURE 1
FIGURE 1
Flow diagram of the literature search and selection procedure.
FIGURE 2
FIGURE 2
Meta-analysis of randomized trials comparing the effect of vasopressin receptor antagonists versus placebo on net change of serum sodium concentration of patients with hyponatremia.
FIGURE 3
FIGURE 3
Meta-analysis of randomized trials comparing the effect of vasopressin receptor antagonists versus placebo on the response rate of patients with hyponatremia.
FIGURE 4
FIGURE 4
Meta-analysis of randomized trials comparing the effect of vasopressin receptor antagonists versus placebo on net change in body weight of patients with hyponatremia.
FIGURE 5
FIGURE 5
Meta-analysis of randomized controlled trials comparing the effect of vasopressin receptor antagonists versus placebo on 24-hour urine output of patients with hyponatremia.
FIGURE 6
FIGURE 6
Random effects meta-analysis of vasopressin receptor antagonists versus placebo for safety. ADR = overall adverse events, CDP = change from baseline in supine diastolic blood pressure, CPC = change from baseline in serum potassium concentration, CPO = change from baseline in plasma osmolality, CSP = change from baseline in supine systolic blood pressure, CUO = change from baseline in urine osmolality, DAE = discontinuations due to adverse events, DCT = discontinuations, DEA = death, DRE = drug-related adverse events, SAE = serious adverse events, trials (patients) = the number of included studies and included patients.

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