Table S1 Search Strategies
Database / Search terms usedMedline / 1. Kidney Diseases/
2. exp Renal Replacement Therapy/
3. Renal Insufficiency/
4. exp Renal Insufficiency, Chronic/
5. dialysis.tw.
6. (hemodialysis or haemodialysis).tw.
7. (hemofiltration or haemofiltration).tw.
8. (hemodiafiltration or haemodiafiltration).tw.
9. (end-stage renal or end-stage kidney or endstage renal or endstage kidney).tw.
10. (ESRF or ESKF or ESRD or ESKD).tw.
11. (chronic kidney or chronic renal).tw.
12. (CKF or CKD or CRF or CRD).tw.
13. (CAPD or CCPD or APD).tw.
14. (predialysis or pre-dialysis).tw.
15. or/1-14
16. exp Heart Failure/
17. (heart adj2 failure*).tw.
18. (congestive adj2 heart).tw.
19. (cardiac adj2 failure*).tw.
20. (heart adj2 decompensation*).tw.
21. (myocardial adj2 failure*).tw.
22. paroxysmal dyspnea*.tw.
23. cardiac asthma.tw.
24. cardiac edema*.tw.
25. or/16-24
26. 15 and 25
27. exp Receptors, Vasopressin/
28. vasopressin*.tw.
29. antagonist*.tw.
30. $vaptan*.tw.
31. 28 and 29
32. 27 or 30 or 31
33. 25 and 32
CENTRAL / #1 dialysis:ti,ab,kw
#2 h*emofiltration:ti,ab,kw
#3 h*emodiafiltration:ti,ab,kw
#4 (end-stage renal or end-stage kidney or endstage renal or endstage kidney):ti,ab,kw
#5 (ESRF or ESKF or ESRD or ESKD):ti,ab,kw
#6 (chronic kidney or chronic renal):ti,ab,kw
#7 (CKF or CKD or CRF or CRD):ti,ab,kw
#8 (CAPD or CCPD or APD):ti,ab,kw
#9 (predialysis or pre-dialysis):ti,ab,kw
#10 MeSH descriptor: [Kidney Failure, Chronic] this term only
#11 MeSH descriptor: [Renal Replacement Therapy] explode all trees
#12 MeSH descriptor: [Renal Insufficiency, Chronic] explode all trees
#13 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12
#14 MeSH descriptor Heart Failure explode all trees
#15 heart near/6 failure*
#16 congestive near/6 heart
#17 cardiac near/6 failure*
#18 heart near/2 decompensation
#19 myocardial near/6 failure*
#20 paroxysmal next dyspnea*
#21 cardiac next asthma
#22 cardiac next edema*
#23 (#14 or #15 or #16 or # 17 or #18 or #19 or #20 or #21 or #22)
#24 #13 and #23
#25 MeSH descriptor: [Receptors, Vasopressin] explode all trees
#26 vasopressin near antagonist
#27 *vaptan*
#28 #25 or #26 or #27
#29 #23 and #28
Figure S1: Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Table S2 – Included studies description
Study ID / Study type / Comparison / N / Follow-up / Inclusion criteria / EndpointsAbraham 2006 [20] / Randomized, double-blind, placebo-controlled / Different doses of lixivaptan vs placebo / 42 / 24 hours / NYHA functional class II or III systolic heart failure (LVEF <35%) / Urine flow
Urine osmolality
Solute-free water excretion
Serum osmolality, serum sodium, serum electrolytes
Plasma concentration of vasopressin and other hormones
Aronson 2011 [21] / Multicentre,
Randomized, double-blind, placebo-controlled study / Different doses of satavaptan vs placebo / 118 / 4 days / Dilution hyponatraemia not caused by SIADH or cirrhosis / Change in serum sodium level
Change in body weight
Udelson 2011 [28] / Placebo vs monotherapy with tolvaptan vs monotherapy with furosemide vs both tolvaptan and furosemide / 83 / 7 days / HF NYHA II-III, LVEF ≤0.40) and signs of congestion / Change in urine output
Change in body weight
Serum sodium and potassium
Udelson 2001 [26] / Randomized double-blind, short-term study / Conivaptan vs placebo / 142 / 12 hours / Decompensated HF patients III or IV NYHA / Change in pulmonary capillary wedge pressure
Change in urine output
Changes in cardiac index, systemic and pulmonary vascular resistance, blood pressure, and heart rate
Matsuzaki 2011 [24] / Phase III, multicenter, randomized, double-blind, placebo-controlled parallel study / Tolvaptan
vs placebo / 122 / 7 days / HF patients with volume overload despite the use of conventional diuretics / Change in body weight
Improvements in signs and symptoms of heart failure
Costello 2006 [30] / Placebo controlled, crossover / Single dose
tolvaptan (30 mg orally daily)
until day 3, and then crossover
for 5 d total; at day 5, all
patients received furosemide 80 mg orally daily / 14 / 5 days / Class II/III HF patients / Parameters of renal function (diuresis, renal blood flow)
Ghali 2012 [11] / Phase II, randomized, double-blind, placebo-controlled, parallel group / Lixivaptan 100 mg vs placebo / 170 / 8 weeks / NYHA I, II, III, IV / Changes in body weight
Renal function
Improvements in signs and symptoms of heart failure
The Trail-making Test, part B (TMT-BMedical Outcomes Survey 6-item cognitive function scale (MOS-6)
Gheorghiade 2004 [25] / Multicenter, placebo
controlled, double
blind / Tolvaptan
30, 60, or 90 mg orally daily vs placebo / 319 / 9 weeks / Decompensated HF patients with LVEF
<40% and 2 clinical signs of volume overload / Measurement of body weight at 24 hours;
Worsening heart failure (defined as death, hospitalization, or unscheduled visits for heart failure) at 60 days
EVEREST trial [22] / Multicenter, placebo
controlled, double
blind / Tolvaptan 30 mg vs placebo / 4133 / 39.6 weeks / Decompensated HF
patients with
LVEF < 40% / Primary end-points: all-cause mortality, CV death or hospitalization for heart failure
Secondary end points included changes in dyspnea, body weight, and edema.
Goldsmith 2008 [29] / Double-blind, multicenter trial / Conivaptan or placebo / 170 / 3 days / Acute decompensated heart failure / Severity of respiratory symptoms and global status,
Changes in body weight
Changes in urine output
Goldsmith 2011 [31] / Prospective, randomized, crossover study / Conivaptan 20 mg vs Furosemid 160 mg (mean dose) / 8 / 3 days / Chronic stable HF / Hemodynamic variable
Neurohormonal level
Renal blood flow
Glomerular filtration rate
Udelson 2008 [27] / Placebo controlled, double
blind, / Different doses of tolvaptan vs placebo / 181 / 8 hours / Decompensated HF patients III or IV NYHA, with LVEF
<40% / Change in pulmonary capillary wedge pressure ; Changes in cardiac index,
Renal and electrolyte parameters (urine volume and osmolarity, sodium, potassium levels)
Inomata 2011 [23] / Phase III, multicentre, randomized, double-blind, parallel group study / Tolvaptan 7.5 mg vs Tolvaptan 15 mg / 23 / 7 days / HF patients with volume overload that had not resolved despite receiving furosemide / Water excretion
Body weight
Table S3-Baseline patient’s characteristic in the included studies
Study ID / N / Age, years, mean,± SD / Sex, male, no % / NYHA class / Cardiovascular assessment / Left ventricular ejection fraction, % (± mean, SD) / Diabetes mellitus / Renal function
(creatinine/GFR) / Baseline sodium mEq/l or mmol/l (±mean, SD) / Fluid restriction / Medication during the study
Abraham 2006 [20] / 42 / Placebo:
55.8
Lixivaptan 10 mg: 58.8
Lixivaptan 400 mg: 51.8 / Placebo: 67%
Lixivaptan 10 mg: 80%
Lixivaptan 400 mg: 60% / II, III / NS / ≤ 35% / NS / NS / 120-140 mmol/l / yes / No other medication was allowed with the exception of digitalis.
Ghali 2012 [11] / 170 / 70 (mean overall group age) / 63.5% / II, III / Peripheral edema, JVD, rales, hepatomegaly, orthopneea / < 40%: 56.5%
≥ 40%: 43.5% / NS / Chronic renal failure (10.6%) / NS / yes / Loop diuretic
ACE inhibitors
Nitrates
ARBs
Digoxin
Aldosterone antagonists
Beta-blockers
Thiazide diuretic
EVEREST trial[22] / 4133 / Placebo: 65.6
Tolvaptan: 65.9 / Placebo: 75.4%
Tolvaptan: 73.4% / III, IV / Dyspnea, orthopnea, rales, pedal edema, JVD / ≤ 40% / yes / yes / NS / NS / Diuretics
ACE inhibitors/ARBs
Beta-blockers
Goldsmith 2011 [31] / 8 / Conivaptan + Furosemide: 51 ± 5.9 / 100% / II, III / NS / 23±7% (averege) / NS / GFR > 30 ml/min/1,73 m2 / yes / ACE inhibitors
ARBs
Inomata 2011 [23] / 23 / Tolvaptan 7.5 mg: 40% < 65 years + 60% ≥ 65 years.
Tolvaptan 15 mg : 40% < 65 years + 60% ≥ 65 years / Tolvaptan 7.5 mg: 40%
Tolvaptan 15 mg: 80% / II, III / Lower limb edema, pulmonary congestion, JVD, hepatomegaly, pulmonary rales / Tolvaptan 7.5 mg: 49.2 (SD 19.5)
Tolvaptan 15 mg: 34.1 (SD 16.6) / NS / NS / NS / no / The following medication was prohibited during the study: Injectable drugs including human atrial natriuretic peptides, phosphodiesterase III inhibitors, catecholamines, colforsinș injectable diureticsș loop diuretics other than furosemide CYP3A4 inhibitors.
Pang 2011 [32] / 4133 / Placebo: 65.6 (SD12.0)
Tolvaptan: 65.9 (SD11.7) / Placebo: 75.4%
Tolvaptan: 73.4 / III, IV / Dyspnea, orthopnea, rales, pedal edema, JVD / Placebo: 27.5 (SD 8.2)
Tolvaptan: 27.5 (SD 8.0) / yes / yes / NS / NS / Diuretics,
ACE inhibitors
ARBs
Beta-blockers
Aldosterone blockers
Udelson 2008 [27] / 181 / Placebo: 58.9 (SD 14)
Tolvaptan 15 mg: 60.3 (SD 11.7)
Tolvaptan 60 mg: 61 (SD 11.9) / Placebo: 83.3%
Tolvaptan 15 mg: 72.7%
Tolvaptan 60 mg: 78.3% / III, IV / NS / Placebo: 24 (SD 9)
Tolvaptan 15 mg: 23(SD 8)
Tolvaptan 60 mg:24 (SD 7) / yes / NS / NS / yes / Diuretics
Beta-blockers
ACE inhibitors
ARBs
Aronson 2011 [21] / 118 / Placebo: 68.8 (SD 11.3)
Satavaptan 25 mg: 68.6 (SD 15.8)
Satavaptan 50 mg: 70.8 (SD11.7) / Placebo: 64.3%
Satavaptan 25 mg: 45.7%
Satavaptan 50 mg: 61.0% / NS / NS / NS / NS / Creatinine clearance:
1. ≥ 80 ml/min:
Placebo: 53.7%
Satavaptan 25 mg:
31.3%
Satavaptan 50 mg: 38.5%
2. 30-50 ml/min:
Placebo: 7.3%
Satavaptan 25 mg: 12.5%
Satavaptan 50 mg: 5.1 % / 1. < 125 mmol/l:
Placebo: 16.7%
Satavaptan 25 mg: 22.9%
Satavaptan 50 mg: 17.1%
2. ≥130 mmol/l:
Placebo: 47.6%
Satavaptan 25 mg: 37.1%
Satavaptan 50 mg: 41.5% / no / Agents acting on renin-angiotensin system
Diuretics
Beta-blockers
Lipid reducing agents
Calcium channel blockers
Antithrombotics
Blood substitutes
Perfusion solutions
Antacids
Mineral supplements
Antidiabetic drugs
Laxatives
Costello 2006 [30] / 14 / 58 (SD8) / 71% / II, III / NS / 34% (SD 3) / NS / GFR was calculated by inulin clearance + effective renal plasma flow – no other data available / NS / No / ACE inhibitors other than captopril were discontinued and replaced with captopril;
- no other medication in rest
Georghiade 2004 [25] / 319 / Placebo: 60 (SD 14)
Tolvaptan 30 mg:
62 (SD 14)
Tolvaptan 90 mg:
62 (14) / Placebo: 75%
Tolvaptan 30 mg:68%
Tolvaptan 90 mg:79.2% / III, IV / JVD, dyspnea, pulmonary rales, edema / Placebo: 25% (SD 7)
Tolvaptan 30 mg: 24% (SD 8)
Tolvaptan 90 mg: 24% (SD 8) / Yes / Placebo: creatinine=1.75 mg/dl (SD 0.27)
Tolvaptan 30 mg: creatinine=2.01 mg/dl (SD 0.85)
Tolvaptan 90 mg: creatinine=2.07 mg/dl (SD 0.85) / Placebo: 139 mEq/l (SD 4.1)
Tolvaptan 30 mg:
138.9 mEq/l (SD 4.3)
Tolvaptan 90 mg: 138.8 mEq/l (SD 4.2) / NS / ACE inhibitors
ARBs
Beta-blockers
Diuretics
Spironolactone
Intravenous inotropes
Calcium channel blockers
Goldsmith 2008 [29] / 170 / Placebo: 63.8 (SD 18)
Conivaptan 40 mg: 60.7 (SD 14.2)
Conivaptan 80 mg:
67.2 (SD 12.0) / Placebo: 60%
Conivaptan 40 mg: 55%
Conivaptan 80 mg:
60% / I, II, III, IV / Dyspnea, jugular venous pressure, pulmonary rales, pleural effusion, third heart sound, cardiac murmur, hepatomegaly, ascites, leg+presacral oedema / Placebo: 25.8% (SD 14.8)
Conivaptan 40 mg: 29.8% (SD 14.8)
Conivaptan 80 mg:
32.2% (SD17.1) / NS / Creatinine measurement – no other data / NS / NS / ACE inhibitors
Beta-blockers
Calcium channel blockers
Digoxin
Diuretics
Matsuzaki 2011 [24] / 122 / Placebo:
- 20-49 years: 1 (SD 3.6
)
- 70-79 years: 16 (SD 57.1)
Tolvaptan overall:
- 20-49 years: 10 (SD 1.2)
- 70-79 years: 36 (40.4) / Placebo: 60.7
Tolvaptan overall: 71.9 / Lower limb edema, pulmonary congestion, pulmonary rales, third cardiac sound, JVD, hepatomegaly / NS / Yes / Assessed, but no other available data / Assessed, but no other available data / NS / During the treatment period, all eligible patients continued their stable furosemide dose (≥40 mg/day).
The use of loop diuretics other than furosemide + human atrial natriuretic peptides, phosphodiesterase III inhibitors, cathecolamines, CYP3A1 inhibitors, CYP3A4 inducing agents was prohibited
Udelson 2011 [28] / 83 / Placebo: 58.0 (SD 9.4)
Tolvaptan: 57.3 (SD 9.0)
Furosemide: 58.8 (SD 14.2)
Tolvaptan+Furosemide: 60.9 (SD 9.3) / Placebo: 90.5
Tolvaptan: 75
Furosemide: 86.4
Tolvaptan+Furosemide: 70 / II, III / NS / Placebo: 27% (SD 7)
Tolvaptan: 22% (SD 9)
Furosemide: 26% (SD 9)
Tolvaptan+Furosemide: 24% (SD 8) / Yes / Placebo: creatinine=1.0 (SD 0.4)
Tolvaptan: creatinine=0.9 (SD 0.2)
Furosemide: creatinine=1.0 (SD0.4)
Tolvaptan+Furosemide: Creatinine=1.0 (SD 0.4 / Placebo: 138.17 (SD 2.79)
Tolvaptan: 137.86 (SD 1.99)
Furosemide: 139 (SD 2.76)
Tolvaptan+Furosemide: 139.20 (SD 3.21) / NS / ACE inhibitors
Diuretics
Beta-blockers
Digoxin
Udelson 2001 [26] / 142 / Placebo: 60 (SD 2)
Conivaptan 10 mg: 58 (SD 2)
Conivaptan 40 mg: 59 (SD 2) / Placebo: 82
Conivaptan 10 mg: 70
Conivaptan 40 mg: 80 / III, IV / NS / Placebo: 23% (SD 4)
Conivaptan 10 mg: 26% (SD 1)
Conivaptan 40 mg: 22% (SD 2) / NS / Placebo: creatinine=1.2 mg/dl (SD 0.1)
Conivaptan 10 mg: creatinine=1.1 mg/dl (SD 0.1)
Conivaptan 40 mg: creatinine=1.3 mg/dl (SD 0.1) / Placebo: 137 (SD 1)
Conivaptan 10 mg: 137 (SD 1)
Conivaptan 40 mg: 137 (1) / Yes / ACE inhibitors
Loop diuretics
Beta-blockers
Spironolactone
Digoxin
NS – not stated;