Effects and safety of natriuretic peptides as treatment of cirrhotic ascites: A systematic review and meta-analysis

Table 1 Main characteristics of the 22 included studies [34 subgroups; receiving bolus injection (n = 8) or continuous infusion (n = 26)]. Atrial natriuretic peptide was tested in 19 studies (215 patients), B-type natriuretic peptide in one study (7 patients), and urodilatin in two studies (21 patients)

Ref.	Country	Study type	Patient n	Drug	Comparator	Adm	Dose (ng/kg/min or ng/kg)	Duration (min)	Post-infusion follow-up (min)	Age (mean)	Male (%)	Ascites severity: Mild/moderate/ severe/refractory	S- or P-sodium (mmol/L) mean ± SE	Quality assessments (risk of bias)
														NOS	RoB2
Abraham et al[31], 1995	United States	Non-random	6	ANP	None	Cont	150	180	180	44.5	67	6/0/0/0	NR	Low	-
			6	ANP	None	Cont	150	180	180	49.5	100	1/3/2/0
Ando[32], 1991	Japan	Non-random	10	ANP	None	Bolus	1000	NA	90	57.1	80	0/5/5/0	138.3 ± 0.7	Low	-
			6	ANP	None	Bolus	1000	NA	90	58.7	67	0/3/3/0	134.2 ± 0.2
Badalamenti et al[33], 1992	Italy	Non-random	9	ANP	None	Bolus	1000	NA	90	57.8	78	0/5/4/0	134.7 ± 1.6	Low	-
			4	ANP	None	Cont	20	60	0	63.3	75	0/3/1/0		Moderate
Carstens et al[36], 1998	Denmark	RCT	15	Urodilatin	Placebo	Cont	20	60	60	50.6	60	15/0/0/0	137.0 ± 0.5	-	Low
Carstens et al[37], 2007	Denmark	RCT	6	Urodilatin	Placebo	Cont	20	90	90	54.0	67	0/0/0/6	133.3 ± 2.0	-	Low
Ferrier et al[14], 1989	Switzerland	Non-random	7	ANP	None	Cont	36	60	60	54.3	57	0/7/0/0	NR	Moderate	-
Fried et al[34], 1990	United States/Switzerland	RCT	11	ANP	Placebo	Cont	15	120	90	NR	82	11/0/0/0	NR	-	Moderate
		RCT	8	ANP	Placebo	Cont	30	120	90	NR	88	8/0/0/0
		RCT	9	ANP	Placebo	Cont	60	120	90	NR	89	9/0/0/0
Gerbes et al[35], 1988	Germany	Non-random	4	ANP	None	Cont	50	30	90	NR	NR	NR	NR	Moderate	-
Ginès et al[22], 1992	Spain	Non-random	5	ANP	None	Cont	50	60	0	57.0	60	0/5/0/0	NR	Moderate	-
			11	ANP	None	Cont	50	60	0		73	0/11/0/0
Heim et al[23], 1990	Germany	Non-random	8	ANP	None	Bolus	500	NA	60	54.5	75	0/8/0/0	NR	Low	-
Jespersen et al[12], 1995	Denmark	Non-random	9	ANP	None	Bolus	2000	NA	120	49.0	89	0/7/2/0	NR	Low	-
Laffi et al[15], 1989	Italy	Non-random	8	ANP	None	Bolus	1000	NA	900	56.4	75	0/0/0/8	131.8 ± 2.6	Low	-
Laffi et al[24], 1989	Italy	Non-random	5	ANP	None	Cont	100	45	75	58.0	60	0/5/0/0	NR	Low	-
			4	ANP	None	Cont	100	45	75	56.4	25	0/4/0/0
			6	ANP	None	Cont	100	45	75	54.0	83	0/6/0/0
La Villa et al[16], 1995	Italy	Non-random	7	BNP	None	Cont	13.861	60	60	56.0	57	0/7/0/0	135.0 ± 1.0	Low	-
Legault et al[25], 1993	Canada	Non-random	5	ANP	None	Cont	15	120	120	NR	80	5/0/0/0	139.0 ± 2.0	Low	-
			7	ANP	None	Cont	15	120	120	NR	71	7/0/0/0	133.0 ± 1.0
Miyase et al[26], 1990	Japan	Non-random	6	ANP	None	Bolus	500	NA	90	58.0	NR	6/0/0/0	NR	Low	-
Morali et al[13], 1991	Canada	Non-random	5	ANP	None	Cont	15	120	60	54.0	80	5/0/0/0	133.0 ± 1.0	Low	-
			12	ANP	None	Cont	15	120	60	53.0	67	0/0/0/12	138.0 ± 1.0
Morali et al[11], 1992	Canada	Non-random	6	ANP	None	Cont	15	120	0	56.8	100	0/0/0/6	NR	Low	-
			4	ANP	None	Cont	15	120	0	64.3	100	0/0/0/4
Salerno et al[27], 1988	Italy	Non-random	7	ANP	Placebo	Bolus	1000	NA	60	56.6	100	0/2/5/0	NR	Low	-
Tobe et al[28], 1993	Canada	Non-random	8	ANP	None	Cont	15	120	0	52.4	100	8/0/0/0	NR	Low	-
Tobe et al[29], 1993	Canada	Non-random	6	ANP	None	Cont	15	120	0	58.0	67	0/0/0/6	NR	Low	-
Wong et al[30], 1993	Canada	RCT	3	ANP	Albumin	Cont	15	120	60	58.0	67	3/0/0/0	135.0 ± 5.0	-	Low
			10	ANP	Albumin	Cont	15	120	60	54.0	70	0/0/0/10	134.0 ± 1.0

¹The continuous infusion of B-type natriuretic peptide (BNP) was administered with 4 pmol/kg/min. The dose was converted to ng/kg/min using the molar mass of BNP.

RCT: Randomised controlled trial; Non-random: Non-randomised trial; ANP: Atrial natriuretic peptide; BNP: B-type natriuretic peptide; NOS: Newcastle-Ottawa-Scale; ROB2: Risk of bias tool version 2; Adm: Mode of administration; Cont: Continuous infusion; S- or P-sodium: Serum or plasma sodium; NR: Not reported; NA: Not applicable.

Table 2 Effect of natriuretic peptides as treatment of cirrhotic ascites grouped by drug

Outcomes	Anticipated absolute effects (95%CI)		No of participants (study subgroups)	Publication bias			Quality of evidence (GRADE)	Comments
	Baseline	Peak		Egger test	Trim-and-fill1
					Baseline	Peak
Atrial natriuretic peptide
Natriuresis (µmol/min)							Low2,3
Continuous infusion	5.6 (3.7-7.4)	27.0 (19.4-34.7)	152 (23)	P < 0.0001	4.2 (2.1-6.1)	22.9 (14.3-31.5)
Low dose (≤ 30 ng/kg/min)	3.6 (2.0-5.3)	15.6 (8.7-22.4)	89 (13)
High dose (> 30 ng/kg/min)	24.2 (13.8-34.5)	72.5 (41.5-103.5)	63 (10)
Bolus injection	10.3 (4.3-16.2)	18.4 (8.8-28.0)	63 (8)	P < 0.0001	8.0 (1.2-14.8)	5.1 (-6.9-17.1)
Diuresis (mL/min)							Very low2,4
Continuous infusion	1.3 (1.0-1.6)	1.8 (1.2-2.3)	62 (8)	P < 0.0001	1.0 (0.7-1.3)	1.8 (1.3-2.4)
Low dose (≤ 30 ng/kg/min)	1.0 (0.7-1.3)	15.6 (8.7-22.4)	89 (13)
High dose (> 30 ng/kg/min)	1.8 (1.2-2.4)	2.8 (1.8-3.8)	63 (10)
Bolus injection	1.1 (0.8-1.5)	2.3 (1.3-3.2)	63 (8)	P < 0.001	0.7 (0.2-1.1)	2.0 (1.1-2.9)
P-Aldosterone (pmol/L)							Very low2,4
Overall	1182 (879-1484)	739 (553-925)	148 (21)	P < 0.0001	1110 (802-1418)	497 (306-689)
Continuous infusion
Low dose (≤ 30 ng/kg/min)	1895 (929-2861)	1110 (670-1551)	56 (8)
High dose (> 30 ng/kg/min)	753 (491-1015)	607 (412-801)	50 (8)
Bolus injection	1095 (449-1741)	435 (58-812)	42 (5)
P-Renin activity (ng/mL/h)							Very low2,4
Overall	5.0 (3.7-6.2)	5.6 (4.2-6.9)	137 (20)	P < 0.0001	4.4 (3.2-5.6)	3.2 (1.8-4.6)
Continuous infusion
Low dose (≤ 30 ng/kg/min)	5.5 (2.8-8.2)	4.0 (2.2-5.8)	50 (7)
High dose (> 30 ng/kg/min)	2.6 (1.8-3.4)	6.5 (3.7-9.2)	54 (9)
Bolus injection	10.5 (3.8-17.2)	11.0 (2.9-19.1)	33 (4)
Bodyweight	NA	NA	NA	NA	NA	NA	NA	Data too sparse for synthesis and quality assessment
Waist circumference	NA	NA	NA	NA	NA	NA	NA	No available data
P-Osmolality	NA	NA	NA	NA	NA	NA	NA	Data too sparse for synthesis and quality assessment
U-Osmolality	NA	NA	NA	NA	NA	NA	NA	No available data
P-Creatinine	NA	NA	NA	NA	NA	NA	NA	Data too sparse for synthesis and quality assessment
AEs	Risk of any AEs: 20 AEs/70 participants = 29%		70 (10)	NA	NA	NA	NA5	20 AEs were reported in two studies covering 6 study subgroups. 3 studies (4 subgroups) observed no AEs
BP reduction	Subgroups reporting BP drops			NA	NA	NA	NA6	Details outlined in Supplementary Table 2
Continuous infusion	53%		125 (19)
Bolus injection	100%		63 (8)
B-type natriuretic peptide
NA							NA7	Data too sparse for synthesis and quality assessment
Urodilatin8
Natriuresis (µmol/min)	Mean difference (Urodilatin vs Placebo): 75 (-33-183)		21 (2)	NA	Mean difference; NA		Very low2,4
Diuresis (mL/min)	Mean difference (Urodilatin vs Placebo): 2.5 (-0.9-5.8)		21 (2)	NA	Mean difference; NA		Very low2,4
AEs	Risk of any AEs: 6 AEs/21 participants = 29%		21 (2)	NA	NA		NA5	6 AEs were reported in the two studies
BP reduction	No BP drops observed for subgroups		21 (2)	NA	NA		NA6	Details outlined in Supplementary Table 2

¹For natriuresis and diuresis trim-and-fill analyses were performed separately for continuous and bolus applications, for all other outcomes exclusively on overall data. Trim-and-fill analyses were restricted to outcomes of atrial natriuretic peptide studies.

²Since the vast majority of studies were non-randomised studies, rating started at low quality of evidence. For ularitide, two cross-over randomised controlled trials were available justifying rating initiation from high quality of evidence. No limitations due to risk of bias, since the majority of included studies obtained a low risk of bias score and the remaining studies a moderate risk of bias (Table 1). Overall results suffered from substantial or considerable heterogeneity with large I². However, the importance of inconsistency for decision-making is uncertain, since the majority of studies were early phase non-randomised clinical trials. Nevertheless, quality of evidence was rated 1 down for the presence of serious inconsistency. Study populations were considered similar without indirectness in interventions.

³Rated 1 up because of a dose-response gradient. Rated 1 up because of large effect defined as a more than two-fold increase in the outcome measure.

⁴Outcomes for atrial natriuretic peptide: Rated 1 down for imprecision due to small sample sizes. Outcomes for urodilatin: Rated 2 down for imprecision due to small sample sizes and the possibility of no effect.

⁵We were unable to estimate quality of evidence for the occurrence of adverse events (AEs), although our results indicated that one atrial natriuretic peptide or urodilatin induced AE may be expected to occur in approximately every fourth patient exposed to the drugs.

⁶We were unable to estimate quality of evidence for the occurrence of blood pressure drops, although our results clearly indicated a frequent occurrence of the event when exposed to atrial natriuretic peptide. For the two urodilatin studies, blood pressure reductions were not observed.

⁷Only one trial with seven participants evaluated the effect of B-type natriuretic peptide and two studies with 21 participants in total evaluated the effect of urodilatin. A justified quality of evidence assessment requires more data.

⁸For urodilatin, data were too sparse for plasma aldosterone concentration and renin activity to justify quality of evidence grading. Furthermore, no data were available for the outcomes bodyweight, waist circumference, plasma and urine osmolality, and plasma creatinine.

Patients or population: Patients with liver cirrhosis and ascites.

Setting: Hospital

Intervention: Intravenous bolus injections or continuous infusions of natriuretic peptides (atrial natriuretic peptide, B-type natriuretic peptide, or urodilatin).

Duration of continuous infusions: 30 to 180 min; Follow-up period bolus injections: 60 to 900 min; Follow-up period continuous infusions: 0 to 180 min; Comparison: Baseline levels/concentrations.

ANP: Atrial natriuretic peptide; BNP: B-type natriuretic peptide; AEs: Adverse events; BP: Blood pressure; NA: Not applicable.