Meta-Analysis
Copyright ©The Author(s) 2022.
World J Hepatol. Apr 27, 2022; 14(4): 827-845
Published online Apr 27, 2022. doi: 10.4254/wjh.v14.i4.827
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 infusion5.6 (3.7-7.4)27.0 (19.4-34.7)152 (23)P < 0.00014.2 (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 injection10.3 (4.3-16.2)18.4 (8.8-28.0)63 (8)P < 0.00018.0 (1.2-14.8)5.1 (-6.9-17.1)
Diuresis (mL/min)Very low2,4
Continuous infusion1.3 (1.0-1.6)1.8 (1.2-2.3)62 (8)P < 0.00011.0 (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 injection1.1 (0.8-1.5)2.3 (1.3-3.2)63 (8)P < 0.0010.7 (0.2-1.1)2.0 (1.1-2.9)
P-Aldosterone (pmol/L)Very low2,4
Overall1182 (879-1484)739 (553-925)148 (21)P < 0.00011110 (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 injection1095 (449-1741)435 (58-812)42 (5)
P-Renin activity (ng/mL/h)Very low2,4
Overall5.0 (3.7-6.2)5.6 (4.2-6.9)137 (20)P < 0.00014.4 (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 injection10.5 (3.8-17.2)11.0 (2.9-19.1)33 (4)
BodyweightNANANANANANANAData too sparse for synthesis and quality assessment
Waist circumferenceNANANANANANANANo available data
P-OsmolalityNANANANANANANAData too sparse for synthesis and quality assessment
U-OsmolalityNANANANANANANANo available data
P-CreatinineNANANANANANANAData too sparse for synthesis and quality assessment
AEsRisk of any AEs: 20 AEs/70 participants = 29%70 (10)NANANANA520 AEs were reported in two studies covering 6 study subgroups. 3 studies (4 subgroups) observed no AEs
BP reductionSubgroups reporting BP dropsNANANANA6Details outlined in Supplementary Table 2
Continuous infusion53%125 (19)
Bolus injection100%63 (8)
B-type natriuretic peptide
NANA7Data too sparse for synthesis and quality assessment
Urodilatin8
Natriuresis (µmol/min)Mean difference (Urodilatin vs Placebo): 75 (-33-183)21 (2)NAMean difference; NAVery low2,4
Diuresis (mL/min)Mean difference (Urodilatin vs Placebo): 2.5 (-0.9-5.8)21 (2)NAMean difference; NAVery low2,4
AEsRisk of any AEs: 6 AEs/21 participants = 29%21 (2)NANANA56 AEs were reported in the two studies
BP reductionNo BP drops observed for subgroups21 (2)NANANA6Details 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.