Interventions for chronic non‐hypovolaemic hypotonic hyponatraemia

Evi V Nagler; Maria C Haller; Wim Van Biesen; Raymond Vanholder; Jonathan C Craig; Angela C Webster

doi:10.1002/14651858.CD010965.pub2

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 4

Effect of baseline serum sodium concentration on change in natraemia: meta‐regression

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Figure 5

Funnel plot of comparison: 1 Vasopressin receptor antagonists versus placebo or no treatment, outcome: 1.6 Response in serum sodium concentration.

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Figure 6

Single study results

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Analysis 1.1

Comparison 1 Vasopressin receptor antagonists (VRA) versus placebo or no treatment, Outcome 1 Death at 6 months.

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Analysis 1.2

Comparison 1 Vasopressin receptor antagonists (VRA) versus placebo or no treatment, Outcome 2 Health‐related quality of life.

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Analysis 1.3

Comparison 1 Vasopressin receptor antagonists (VRA) versus placebo or no treatment, Outcome 3 Cognitive function: trail making test Part B.

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Analysis 1.4

Comparison 1 Vasopressin receptor antagonists (VRA) versus placebo or no treatment, Outcome 4 Length of hospital stay.

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Analysis 1.5

Comparison 1 Vasopressin receptor antagonists (VRA) versus placebo or no treatment, Outcome 5 Change from baseline serum sodium concentration.

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Analysis 1.6

Comparison 1 Vasopressin receptor antagonists (VRA) versus placebo or no treatment, Outcome 6 Response in serum sodium concentration.

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Analysis 1.7

Comparison 1 Vasopressin receptor antagonists (VRA) versus placebo or no treatment, Outcome 7 Rapid increase in serum sodium concentration.

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Analysis 1.8

Comparison 1 Vasopressin receptor antagonists (VRA) versus placebo or no treatment, Outcome 8 Hypernatraemia during treatment.

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Analysis 1.9

Comparison 1 Vasopressin receptor antagonists (VRA) versus placebo or no treatment, Outcome 9 Thirst.

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Analysis 1.10

Comparison 1 Vasopressin receptor antagonists (VRA) versus placebo or no treatment, Outcome 10 Other adverse events.

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Analysis 1.11

Comparison 1 Vasopressin receptor antagonists (VRA) versus placebo or no treatment, Outcome 11 Injection‐site complications at 2 to 7 days.

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Analysis 1.12

Comparison 1 Vasopressin receptor antagonists (VRA) versus placebo or no treatment, Outcome 12 Treatment discontinuation.

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Analysis 1.13

Comparison 1 Vasopressin receptor antagonists (VRA) versus placebo or no treatment, Outcome 13 Death during follow‐up: sensitivity analysis.

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Analysis 1.14

Comparison 1 Vasopressin receptor antagonists (VRA) versus placebo or no treatment, Outcome 14 Rapid increase in serum sodium concentration: sensitivity analysis.

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Summary of findings for the main comparison. Vasopressin receptor antagonists versus placebo or no treatment for chronic non‐hypovolaemic hypotonic hyponatraemia

Vasopressin receptor antagonists versus placebo or no treatment for chronic non‐hypovolaemic hypotonic hyponatraemia
Patient or population: chronic non‐hypovolaemic hypotonic hyponatraemia Intervention: Vasopressin receptor antagonists Comparison: placebo or no treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo or no treatment	Vasopressin receptor antagonists
Death Follow‐up: range 2 to 180 days	Study population		RR 1.11 (0.92 to 1.33)	2330 (15)	⊕⊝⊝⊝ VERY LOW ^{2, 3}	Interpretation: effect uncertain; may both result in 11/1000 fewer to 47/1000 more deaths within 6 months
	143 per 1000 ¹	159 per 1000 (132 to 190)
Health‐related quality of life (assessed with mental component score of SF‐12⁴) Follow‐up: 30 days	The mean change from baseline in health‐related quality of life in the control group ranged between 0.75 and 2.39 on a 0 to 100 point scale (worst to best) ⁵	The mean health‐related quality of life in the intervention group was 4.76 higher (0.11 higher to 9.41 higher)	‐	297 (2)	⊕⊝⊝⊝ VERY LOW ^{6, 7}	Physical component score also measured in both studies; RR 1.04; CI ‐1.81 to 3.90 Interpretation: anywhere from 0.1 to 9.5/100 points higher increase with treatment, but questionable tool for QoL measurement in hyponatraemia and unclear minimally important clinical difference
Length of hospital stay	The mean length of hospital stay in the control group was 6 to 11 days ⁵	The mean length of hospital stay in the intervention group was 1.63 days lower (2.96 lower to 0.30 lower)	‐	580 (2)	⊕⊕⊝⊝ LOW ^8,9
Cognitive function (assessed with various tools) Follow‐up: 1 to 6 months		Across five studies, confidence intervals spanned the line of no effect and did not include a clinically meaningful effect	‐	1169 (5)	⊕⊕⊝⊝ LOW ¹⁰	Tools used to assess cognitive function: making test B; reaction time, psychomotor, processing speeds; Mini mental state exam; overall meta‐analysis including all five studies not meaningfully possible
Change from baseline in serum sodium concentration Follow‐up: range 1 to 180 days	The mean change from baseline in serum sodium concentration in the control group was 0.3 to 4.8 mmol/L ⁵	The mean change from baseline in serum sodium concentration in the intervention group was 4.17 mmol/L higher (3.18 higher to 5.16 higher)	‐	2641 (21)	⊕⊕⊕⊝ MODERATE ¹¹
Serum sodium concentration (response) Follow‐up: range 4 to 180 days	Study population		RR 2.49 (1.95 to 3.18)	2104 (18)	⊕⊕⊕⊝ MODERATE ¹¹	Response most commonly defined by investigators as > 5 to > 6 mmol/L increase or normalisation of serum sodium concentration
	231 per 1000 ¹	576 per 1000 (454 to 597)
Rapid sodium increase Follow‐up: range 1 to 5 days	Study population		RR 1.67 (1.16 to 2.40)	2058 (14)	⊕⊕⊕⊝ MODERATE ¹²	Rapid increase most commonly defined as > 12 mmol/d
	44 per 1000 ¹	73 per 1000 (51 to 105)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Very low quality: We are very uncertain about the estimate
¹ Source of assumed baseline risk was calculated as the unweighted summed event rate in the control groups of the trials included in the meta‐analysis ² Downgraded one level because studies considered at serious risk of suffering from * selective reporting: 6/16 studies with treatment duration > 1 week did not report death and had no protocol, accounting for 16% of the total number of participants in those studies * commercial sponsorship; possible financial conflict of interest of the authors: all studies sponsored by pharmaceutical companies wanting to commercialize the treatment; all save one had author lists who featured people who had received money for presentations or consultancy, or were employed by the sponsor; only used as supporting reason for downgrading. ³ Downgraded two levels for imprecision. The 95% CI of the pooled estimate includes both important reduction (11/1000 fewer) and increase (47/1000 more) in death with vasopressin receptor antagonists. ⁴ Choice of the outcome‐measure based on the fact that this was the only one reported in any of the studies. There are concerns around the validity of the SF‐12 as a measure for health‐related quality of life in the field of hyponatraemia as it gauges domains and symptoms not directly attributable to hyponatraemia. ⁵ Source of the assumed baseline risk was the range of outcomes in the control groups of the trials included in the meta‐analysis ⁶ Downgraded one level because studies considered seriously at risk of suffering from * Performance bias: self‐reported outcome, participants likely unblinded to treatment due to polyuria as side effect * Selective reporting bias: both mental and physical component score of SF‐12 measured; at week 1 or 2 and day 30 using two different analytic techniques. Only data at day 30 available for analysis. * Attrition bias: overall 37% of data missing, unknown whether missing at random or not. * Commercial sponsorship or possible financial conflict of interest of authors: both studies were sponsored by the company seeking to commercialise the treatment; both had author lists who featured people who had received money for presentations or consultancy, or were employed by the sponsor; only using as supporting argument for downgrading ⁷ Downgraded one level for indirectness due to concerns around validity of the SF‐12 for measuring quality of life in the context of hyponatraemia and one level for imprecision: only studied in two studies. ⁸ Downgraded one level because studies considered seriously at risk of suffering from performance bias: participants and personnel likely unblinded to treatment due to polyuria as side effect; this could have influenced self‐reported and professional appreciation of clinical condition and so have influenced decision to discharge from hospital. ⁹ Downgraded one level for imprecision. The 95% CI of the pooled estimate includes both negligible shortening (0.3 days shorter) and clinically important shortening (3 days shorter) of hospital stay with vasopressin receptor antagonists. ¹⁰ Downgraded two levels for indirectness and imprecision. Only studied in 5/28 studies, with most data for lixivaptan, and other studies not reaching the optimal information size. ¹¹ Downgraded one level because we considered studies seriously at risk of suffering from * Attrition bias: 7/21 studies, accounting for 53% of the total number of participants in those studies at high risk of bias either due to true attrition or because a repeated measures analytic technique was used with all measurements of serum sodium concentration included until patient attrition, which we judged would likely have overestimated the treatment effect. *Commercial sponsorship; only used as supporting argument. ¹² Downgraded one level for indirectness; risks controlled in tightly organised randomised trial with several measurements of serum sodium concentration daily to avoid rapid correction. In real life, risk of rapid correction likely greater. Commercial sponsorship bias; only used as supporting argument.

Summary of findings for the main comparison. Vasopressin receptor antagonists versus placebo or no treatment for chronic non‐hypovolaemic hypotonic hyponatraemia

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Table 1. Change in serum sodium concentration: meta‐regression and confounding

Covariate	Number of studies included in meta‐regression	Scale	Absolute change in mean difference	P value
Baseline serum sodium concentration	21	Per 1 mmol/L increase	‐0.33 (‐0.65 to ‐0.02)	0.04
Compound	21	Relative to conivaptan	‐	0.17
Conivaptan	5	‐	‐	‐
Lixivaptan	4	‐	‐2.79 (‐5.47 to ‐0.10)	‐
Satavaptan	3	‐	‐0,23 (‐3.34 to 2.87)	‐
Tolvaptan	9	‐	‐0.82 (‐3.13 to 1.50)	‐
Cause of hyponatraemia	21	Relative to SIADH	‐	0.18
SIADH	5	‐	‐	‐
Combined SIADH ‐ Heart failure, cirrhosis	10	‐	0.67 (‐1.77 to 3.13)	‐
Heart failure	6	‐	‐1.19 (‐3.84 to 1.47)	‐
Treatment duration	21	Per day increase	‐0.02 (‐0,04 to 0.00)	0.1
Risk of selection bias	21	Relative to low risk	‐	0.86
Low risk	8	‐	‐	‐
High risk	13	‐	0.18 (‐1.90 to 2.27)	‐

Table 1. Change in serum sodium concentration: meta‐regression and confounding

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Comparison 1. Vasopressin receptor antagonists (VRA) versus placebo or no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death at 6 months Show forest plot	15	2330	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.92, 1.33]

1.1 Conivaptan	4	222	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.13, 1.17]
1.2 Lixivaptan	3	950	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.85, 1.80]
1.3 Tolvaptan	8	1158	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.89, 1.39]
2 Health‐related quality of life Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

2.1 Mental component SF‐12	2	297	Mean Difference (IV, Random, 95% CI)	4.76 [0.11, 9.41]
2.2 Physical component SF‐12	2	300	Mean Difference (IV, Random, 95% CI)	1.04 [‐1.81, 3.90]
3 Cognitive function: trail making test Part B Show forest plot	2	858	Mean Difference (IV, Random, 95% CI)	6.89 [‐6.34, 20.12]

4 Length of hospital stay Show forest plot	3	610	Mean Difference (IV, Random, 95% CI)	‐1.63 [‐2.96, ‐0.30]

4.1 Satavaptan	1	139	Mean Difference (IV, Random, 95% CI)	‐1.80 [‐3.80, 0.20]
4.2 Tolvaptan	2	471	Mean Difference (IV, Random, 95% CI)	‐1.50 [‐3.28, 0.29]
5 Change from baseline serum sodium concentration Show forest plot	21	2641	Mean Difference (IV, Random, 95% CI)	4.17 [3.18, 5.16]

5.1 Conivaptan	5	292	Mean Difference (IV, Random, 95% CI)	5.17 [2.65, 7.69]
5.2 Lixivaptan	4	1070	Mean Difference (IV, Random, 95% CI)	2.24 [0.78, 3.70]
5.3 Satavaptan	3	257	Mean Difference (IV, Random, 95% CI)	4.91 [2.88, 6.94]
5.4 Tolvaptan	9	1022	Mean Difference (IV, Random, 95% CI)	4.22 [3.55, 4.89]
6 Response in serum sodium concentration Show forest plot	18	2104	Risk Ratio (M‐H, Random, 95% CI)	2.49 [1.95, 3.18]

6.1 Conivaptan	4	282	Risk Ratio (M‐H, Random, 95% CI)	2.48 [1.54, 4.01]
6.2 Lixivaptan	4	1024	Risk Ratio (M‐H, Random, 95% CI)	2.21 [1.19, 4.10]
6.3 Satavaptan	4	331	Risk Ratio (M‐H, Random, 95% CI)	3.33 [1.88, 5.89]
6.4 Tolvaptan	6	467	Risk Ratio (M‐H, Random, 95% CI)	2.36 [1.75, 3.18]
7 Rapid increase in serum sodium concentration Show forest plot	14	2058	Risk Ratio (M‐H, Random, 95% CI)	1.67 [1.16, 2.40]

7.1 Conivaptan	4	290	Risk Ratio (M‐H, Random, 95% CI)	3.77 [0.89, 15.98]
7.2 Lixivaptan	4	994	Risk Ratio (M‐H, Random, 95% CI)	1.39 [0.90, 2.17]
7.3 Satavaptan	4	331	Risk Ratio (M‐H, Random, 95% CI)	2.61 [0.73, 9.30]
7.4 Tolvaptan	2	443	Risk Ratio (M‐H, Random, 95% CI)	6.70 [0.82, 54.56]
8 Hypernatraemia during treatment Show forest plot	10	1592	Risk Ratio (M‐H, Random, 95% CI)	1.37 [0.63, 3.01]

8.1 Conivaptan	1	83	Risk Ratio (M‐H, Random, 95% CI)	2.87 [0.14, 57.89]
8.2 Lixivaptan	2	306	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.04, 5.78]
8.3 Satavaptan	3	262	Risk Ratio (M‐H, Random, 95% CI)	1.98 [0.35, 11.11]
8.4 Tolvaptan	4	941	Risk Ratio (M‐H, Random, 95% CI)	2.73 [0.81, 9.22]
9 Thirst Show forest plot	13		Odds Ratio (Random, 95% CI)	2.77 [1.80, 4.27]

10 Other adverse events Show forest plot	17		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

10.1 Polyuria	6	1272	Risk Ratio (M‐H, Random, 95% CI)	4.69 [1.59, 13.85]
10.2 Hypotension	14	1748	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.75, 1.63]
10.3 Acute kidney injury	8	1920	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.67, 1.18]
10.4 Liver function abnormalities	3	811	Risk Ratio (M‐H, Random, 95% CI)	2.43 [0.88, 6.70]
11 Injection‐site complications at 2 to 7 days Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

11.1 Reactions	1	49	Risk Ratio (M‐H, Random, 95% CI)	7.56 [0.49, 115.93]
11.2 Phlebitis	2	133	Risk Ratio (M‐H, Random, 95% CI)	3.52 [1.00, 12.41]
11.3 Thrombosis	2	133	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.21, 14.80]
12 Treatment discontinuation Show forest plot	14	2429	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.85, 1.00]

12.1 Conivaptan	4	288	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.39, 1.30]
12.2 Lixivaptan	4	1008	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.84, 1.03]
12.3 Satavaptan	2	145	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.17, 1.46]
12.4 Tolvaptan	4	988	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.66, 1.13]
13 Death during follow‐up: sensitivity analysis Show forest plot	16	2404	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.91, 1.32]

13.1 Conivaptan	5	296	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.19, 1.15]
13.2 Lixivaptan	3	950	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.37, 3.15]
13.3 Tolvaptan	8	1158	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.89, 1.39]
14 Rapid increase in serum sodium concentration: sensitivity analysis Show forest plot	14	2058	Risk Ratio (M‐H, Random, 95% CI)	1.67 [1.16, 2.40]

14.1 > 8 mmol/L/d	4	257	Risk Ratio (M‐H, Random, 95% CI)	3.22 [0.65, 15.94]
14.2 > 12 mmol/L/d	10	1801	Risk Ratio (M‐H, Random, 95% CI)	1.63 [1.09, 2.43]

Comparison 1. Vasopressin receptor antagonists (VRA) versus placebo or no treatment

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