Impact of an acute hemodynamic response-guided protocol for primary prophylaxis of variceal bleeding

Table 1 Baseline characteristics of patients

Variable1	Acute responders, n = 52	Acute nonresponders, n = 24	P value
Age in yr	57.8 ± 10.2	57.1 ± 8.7	0.764
Sex (male)	40 (76.9)	19 (79.2)	1
Body mass index	28.6 ± 5.0	28.5 ± 4.8	0.918
Associated diseases2	34 (65.4)	16 (66.7)	1
Regular medication
Statins	3 (5.8)	3 (12.5)	0.373
Metformin	10 (19.2)	5 (20.8)	1
Antiplatelet agent	7 (13.5)	1 (4.2)	0.423
Anticoagulation	2 (3.8)	0 (0)	1
Etiology of liver disease3			0.971
Alcohol	34 (65.4)	17 (70.8)	0.794
Hepatitis C	4 (7.7)	2 (8.3)	1
Alcohol + hepatitis C	4 (7.7)	2 (8.3)	1
Other	10 (19.2)	3 (12.6)	0.744
Active alcoholism
At first hemodynamic study	11 (27.5)	4 (20.0)	0.753
During follow-up	3 (7.9)	2 (10.5)	1
Active hepatitis C
At first hemodynamic study	8 (100)	4 (100)	1
During follow-up	4 (50)	2 (50.0)	1
Esophageal varices	49 (94.2)	21 (87.5)	0.310
Small	3 (6.1)	3 (14.3)	0.355
Large	46 (93.9)	18 (85.7)
Gastric varices	3 (5.8)	3 (12.5)	0.373
Red signs	10 (20.0)	3 (13.6)	0.742
Hemoglobin in g/dL	12.7 ± 2.1	12.7 ± 2.2	0.994
Platelet count as × 103/μL	102 ± 45	122 ± 53	0.100
Prothrombin time as INR	1.36 ± 0.24	1.39 ± 0.26	0.685
Bilirubin in mg/dL3	1.7 ± 1.1	2.8 ± 4.5	0.235
Albumin in g/dL3	3.6 ± 0.6	3.6 ± 0.6	0.878
Creatinine in mg/dL	0.72 ± 0.24	0.73 ± 0.24	0.900
Sodium in mEq/L	139 ± 3	138 ± 4	0.108
Hyponatremia (< 135)	3 (6.0)	5 (20.8)	0.103
Ascites	31 (59.6)	14 (58.3)	1
Refractory ascites	1 (1.9)	1 (4.2)	0.535
Hepatic encephalopathy	8 (15.4)	4 (16.7)	1
Spontaneous bacterial peritonitis	4 (7.7)	0 (0)	0.301
Hepatocellular carcinoma	3 (5.8)	1 (4.2)	1
No previous decompensation	21 (40.4)	9 (37.5)	1
MELD	11.5 ± 3.2	12.3 ± 4.4	0.353
Child-Pugh score	6.5 ± 1.4	6.7 ± 1.6	0.560
A/B/C, %	58/40/2	50/42/8	0.388
Propranolol dose in acute test in mg	12.1 ± 2.4	12.6 ± 2.8	0.44
Free hepatic venous pressure in mmHg	10.8 ± 4.3	11.7 ± 4.7	0.386
Change from baseline, %	+18.5 ± 23.5	+3.4 ± 11.2	< 0.001
Wedged hepatic venous pressure in mmHg	30.0 ± 5.4	30.4 ± 5.5	0.581
Change from baseline, %	-6.6 ± 5.3	-1.2 ± 6.3	< 0.001
Hepatic venous pressure gradient in mmHg3	18.8 ± 3.7	18.7 ± 3.7	0.854
Change from baseline, %	-17.8 ± 7.7	-3.9 ± 5.6	< 0.001
Decrease by > 10%, %	96.2	0	< 0.001
Decrease to < 12 mmHg, %	23.1	0	0.014
Mean arterial pressure in mmHg	99 ± 9	95 ± 11	0.145
Change from baseline, %	-5.6 ± 12.2	+2.7 ± 9.7	0.008
Heart rate as bpm	78 ± 13	81 ± 15	0.315
Change from baseline, %	-18.8 ± 8.5	-19.4 ± 7.3	0.779
Right atrial pressure in mmHg	7.0 ± 2.9	7.3 ± 3.8	0.712
Change from baseline, %	+51.4 ± 41.1	+45.1 ± 45.3	0.565
Pulmonary arterial pressure in mmHg	18.3 ± 4.9	17.8 ± 5.0	0.700
Change from baseline, %	+18.6 ± 18.9	+16.1 ± 14.9	0.606
Pulmonary wedge pressure in mmHg	11.8 ± 4.1	11.4 ± 5.0	0.711
Change from baseline, %	+28.3 ± 37.2	+38.4 ± 54.9	0.384

¹Quantitative variables were expressed as mean ± SD and qualitative variables as absolute value (proportion);

²Associated diseases: hypertension, diabetes mellitus, dyslipidemia, coronary artery disease, chronic renal disease;

³Variables included in the multivariate analysis. INR: International normalized ratio; NSBB: Nonselective beta-blockers.

Table 2 Characteristics of chronic hemodynamic responders and chronic nonresponders in each group

	Traditional NSBB			Carvedilol
Variable1	CR, n = 15	CNR, n = 12	P value	CR, n = 9	CNR, n = 4	P value
Age in yr	58.9 ± 8.3	57.8 ± 10.3	0.766	59.2 ± 9.2	57.3 ± 6.8	0.685
Sex (male)	12 (80.0)	9 (75.0)	1	8 (88.9)	3 (75.0)	1
Body mass index	28.8 ± 2.1	29.1 ± 4.3	0.795	30.5 ± 5.9	28.0 ± 3.6	0.370
Associated diseases2	12 (80.0)	10 (83.3)	1	7 (77.8)	2 (50)	0.530
Regular medication
Statins	2 (13.3)	1 (8.3)	1	2 (22.2)	0 (0)	1
Metformin	3 (20)	2 (16.7)	1	1 (11.1)	2 (50.0)	0.203
Antiplatelet agent	1 (6.7)	3 (25)	0.294	0 (0)	0 (0)	1
Anticoagulation	1 (6.7)	1 (8.3)	1	0 (0)	0 (0)	1
Etiology of liver disease			0.063			1
Alcohol	14 (93.3)	6 (50.0)	0.024	8 (88.9)	4 (100)	1
Hepatitis C	0 (0)	2 (16.7)	0.188	0 (0)	0 (0)	1
Alcohol + hepatitis C	0 (0)	2 (16.7)	0.188	0 (0)	0 (0)	1
Other	1 (6.7)	2 (16.6)	0.569	1 (11.1)	0 (0)	1
Active alcoholism	0 (0)	1 (9.1)	0.440	1 (12.5)	1 (25.0)	1
Active hepatitis C	0 (0)	0 (0)	1	0 (0)	0 (0)	1
Esophageal varices	14 (93.3)	11 (91.7)		6 (66.7)	4 (100)
Small, %	0	0	1	33.3	0	0.467
Large, %	100	100		66.7	100
Gastric varices	1 (6.7)	1 (8.3)	1	3 (33.3)	0 (0.0)	0.497
Red signs	3 (20.0)	1 (8.3)	0.605	1 (12.5)	1 (25.0)	1
Baseline MELD	11.5 ± 2.9	11.0 ± 3.4	0.660	12.3 ± 6.3	12.8 ± 1.0	0.852
Change from baseline, %	-4.1 ± 14.2	0.8 ± 16.8	0.426	-0.8 ± 28.0	-7.9 ± 14.5	0.565
Baseline Child-Pugh score	6.7 ± 1.4	6.1 ± 1.1	0.225	6.8 ± 2.0	7.0 ± 0.0	0.753
Change from baseline, %	-3.0 ± 12.1	0.3 ± 9.9	0.465	-7.2 ± 13.7	0.0 ± 11.6	0.363
Baseline Child-Pugh class A/B/C, %	53/47/0	42/58/0	1	67/11/22	0/100/0	0.010
Change from baseline A/B/C, %	67/33/0	67/33/0	1	67/33/0	75/25/0	0.266
Hemoglobin in g/dL	12.8 ± 2.1	14.0 ± 2.2	0.150	12.8 ± 2.0	14.5 ± 2.7	0.319
Platelet count as × 103/μL	107 ± 35	86 ± 27	0.102	91 ± 32	114 ± 41	0.367
Prothrombin time as INR	1.37 ± 0.18	1.32 ± 0.15	0.498	1.28 ± 0.21	1.35 ± 0.04	0.358
Bilirubin in mg/dL	1.3 ± 0.7	1.6 ± 0.8	0.349	1.57 ± 0.96	1.93 ± 1.19	0.619
Albumin in g/dL	3.5 ± 0.5	3.7 ± 0.4	0.397	3.9 ± 0.4	3.5 ± 0.4	0.080
Creatinine in mg/dL	0.72 ± 0.18	0.78 ± 0.16	0.415	0.71 ± 0.25	0.66 ± 0.05	0.590
Sodium in mEq/L	140 ± 2	140 ± 3	0.342	139 ± 2	139 ± 2	0.638
Ascites	9 (60.0)	6 (50.0)	0.707	5 (55.6)	4 (100)	0.228
Hepatic encephalopathy	4 (26.7)	0 (0)	0.106	0 (0)	1 (25.0)	0.308
SBP	3 (20.0)	0 (0)	0.231	0 (0)	0 (0)	1
Hepatocellular carcinoma	0 (0)	0 (0)	1	0 (0)	0 (0)	1
Hemodynamic variables
Weeks between studies	24.2 ± 12.3	29.1 ± 13.4	0.327	26.2 ± 14.0	31.9 ± 29.4	0.732
Propranolol dose in mg	136 ± 111	165 ± 123	0.677
Nadolol dose in mg	87 ± 47	95 ± 21	0.659
Carvedilol dose in mg				18.8 ± 12.5	14.1 ± 7.9	0.434
FHVP in mmHg	10.0 ± 2.7	11.2 ± 2.4	0.250	11.9 ± 3.9	11.0 ± 2.1	0.583
Change from baseline, %	36.4 ± 62.6	-3.5 ± 30.4	0.054	10.4 ± 31.1	1.8 ± 8.4	0.458
WHVP in mmHg	29.6 ± 2.5	29.0 ± 2.9	0.622	28.5 ± 5.7	31.1 ± 5.1	0.437
Change from baseline, %	-8.5 ± 15.9	0.7 ± 10.6	0.100	-9.5 ± 9.5	5.8 ± 9.2	0.034
HVPG in mmHg	19.5 ± 2.9	17.9 (2.5)	0.126	16.4 ± 2.5	20.1 ± 3.2	0.100
Change from baseline, %	- 26.0 ± 12.5	5.7 ± 17.7	< 0.0001	-21.2 ± 12.8	-7.6 ± 13.3	0.012
Decrease by > 10%	15 (100)	0 (0)	< 0.0001	8 (88.9)	0 (0)	0.007
Decrease < 12 mmHg	3 (20)	0 (0)	0.231	4 (44.0)	0 (0)	0.228
MAP in mmHg	99 ± 9	98 ± 8	0.642	96 ± 12	97 ± 11	0.897
Change from baseline, %	-5.6 ± 7.3	0.3 ± 12.1	0.192	6.6 ± 17.8	-2.0 ± 7.7	0.273
Heart rate as bpm	77 ± 11	77 ± 16	0.902	82 ± 11	76 ± 9	0.311
Change from baseline, %	-26.2 ± 12.5	-19.8 ± 14.9	0.265	-26.8 ± 10.6	-17.1 ± 7.7	0.102
Right atrial pressure in mmHg	6.4 ± 2.1	7.4 ± 2.3	0.264	8.4 ± 5.0	7.0 ± 1.4	0.458
Change from baseline, %	74.2 ± 82.3	24.1 ± 66.5	0.100	35.5 ± 97.2	23.2 ± 27.0	0.733
PAP in mmHg	18.3 ± 4.2	17.9 ± 4.3	0.813	20.1 ± 4.8	17.5 ± 3.1	0.281
Change from baseline, %	35.3 ± 42.8	17.4 ± 27.6	0.222	-4.5 ± 18.7	27.5 ± 43.9	0.242
PWP in mmHg	11.5 ± 3.3	11.8 ± 3.5	0.819	12.8 ± 5.3	12.0 ± 3.2	0.751
Change from baseline, %	50.9 ± 57.5	32.0 ± 61.2	0.417	5.5 ± 37.1	14.8 ± 10.8	0.506

¹Quantitative variables were expressed as mean ± standard deviation and qualitative variables as absolute value (proportion);

²Associated diseases: hypertension, diabetes mellitus, dyslipidemia, coronary artery disease, chronic renal disease. CR: Chronic responder; CNR: Chronic nonresponder; FHVP: Free hepatic venous pressure; HVPG: Hepatic venous pressure gradient; MAP: Mean arterial pressure; PAP: Pulmonary arterial pressure; PWP: Pulmonary wedged pressure; SBP: Spontaneous bacterial peritonitis; WHVP: Wedged hepatic venous pressure.

Table 3 Clinical outcomes during follow-up in patients with acute response treated with traditional nonselective beta-blockers and in patients without acute response treated with carvedilol

Variable1	Traditional NSBB, n = 52	Carvedilol, n = 24	P value
Decompensation (global)2	12 (23.1)	8 (33.3)	0.405
First decompensation	3 (14.3)	2 (22.2)	0.622
Further decompensation	9 (29.0)	6 (40.0)	0.514
Portal hypertension-related bleeding	2 (3.8)	3 (12.5)	0.318
Ascites
Overall	7 (13.5)	4 (16.7)	0.734
De novo ascites	3 (5.8)	1 (4.2)	1
Spontaneous bacterial peritonitis	1 (1.9)	2 (8.3)	0.233
Hepatorenal syndrome	1 (1.9)	1 (4.2)	0.535
Hepatic encephalopathy
Overall	7 (13.5)	5 (20.8)	0.502
De novo hepatic encephalopathy	3 (5.8)	4 (16.7)	0.191
Hepatocellular carcinoma (de novo)	3 (6.1)	0 (0)	0.546
Portal thrombosis	5 (9.6)	3 (12.5)	0.702
Nonselective beta-blocker
Propranolol dose, n/mg per day	35 / 107.6
Nadolol dose, n/mg per day	17 / 83.5
Carvedilol dose, n/mg per day		24 / 9.2
Chronic hemodynamic response
Change from baseline HVPG, %	-11.9 ± 21.8	-12.2 ± 18.5	0.965
≥ 10% reduction in HVPG	15 (55.6)	9 (69.2)	0.503
≥ 20% reduction in HVPG	8 (29.6)	4 (30.8)	1
Decrease to < 12 mmHg	3 (11.1)	4 (30.8)	0.187
Lost to follow-up, n/%	14 (26.9)	3 (12.5)	0.238
Betablocker intolerance	6 (11.5)	1 (4.2)	0.421
Change to carvedilol after second hemodynamic study	5 (7.7)
Ceased follow-up	3 (5.8)	2 (8.3)	0.648

¹Quantitative variables were expressed as mean ± standard deviation and qualitative variables as absolute value (proportion);

²Decompensation: Development of de novo or worsening ascites, hepatic encephalopathy, portal hypertension-related bleeding, hepatorenal syndrome or spontaneous bacterial peritonitis. The number of decompensation events in each group is lower than the total sum of each complication because some patients suffered more than one complication during follow-up. NSBB: Nonselective beta-blockers.

Table 4 Results of univariate and multivariate analyses for variables associated with risk of decompensation

Variables	Univariable		Multivariable
	HR (95%CI)	P value	HR (95%CI)	P value
Age as per year increase	0.96 (0.91-1.01)	0.093	0.97 (0.92-1.02)	0.246
Active alcoholism	2.55 (0.71-9.16)	0.152
Size of varices	1.71 (0.23-12.90)	0.602
Red signs	1.89 (0.62-5.73)	0.262
MELD as per 1 point increase1	1.12 (0.99-1.26)	0.072
Child class		0.039		0.071
B vs A	2.66 (1.03-6.87)	0.044	2.39 (0.90-6.36)	0.081
C vs A	5.87 (1.20-28.63)	0.029	6.00 (1.09-32.97)	0.039
Platelets as per 1 × 106	1.00 (0.99-1.01)	0.641
Creatinine as per 1 mg/dL increase	0.17 (0.01-2.74)	0.209
Bilirubin as per 1 mg/dL increase2	1.21 (1.09-1.35)	< 0.001
Albumin as per 1 g/L increase2	0.43 (0.20-0.94)	0.035
INR as per 1 point increase	1.16 (0.20-6.56)	0.871
HVGP as per 1 mmHg increase	1.07 (0.96-1.20)	0.209
MAP as per 1 mmHg increase	0.98 (0.94-1.03)	0.497
Previous ascites2	2.42 (0.88-6.65)	0.088
Previous hepatocellular carcinoma	2.44 (0.55-10.77)	0.240
Previous hepatic encephalopathy	7.29 (2.78-19.13)	< 0.001	8.03 (2.76-23.37)	< 0.001
No previous decompensation1	0.42 (0.15-1.16)	0.093
Acute hemodynamic response	0.70 (0.29-1.71)	0.434	0.74 (0.28-1.95)	0.545
Chronic hemodynamic response-10%	0.49 (0.13-1.83)	0.287
Chronic hemodynamic response-20%	0.24 (0.03-1.89)	0.174

¹To avoid redundancy and due to a more significant association in the univariate analysis of the Child-Pugh class, MELD score and the absence of any previous decompensation were not included in the multivariate analysis;

²History of ascites, serum bilirubin and albumin were not included in the multivariate analysis to avoid redundancy, since they are part of the Child-Pugh score. HR: Hazard ratio; HVPG: Hepatic venous gradient pressure; INR: International normalized ratio; MAP: Mean arterial pressure; MELD: Model of end-stage liver disease.

Table 5 Results of univariate analysis for variables associated with risk of death

Variables	Univariable
	HR (95%CI)	P value
Age as per year increase	1.01 (0.93-1.09)	0.896
Active alcoholism	0.04 (0.00-2577625.31)	0.731
Size of varices	0.28 (0.03-2.55)	0.259
MELD as per 1 point increase	0.91 (0.72-1.16)	0.448
Child score as per 1 point increase	0.98 (0.59-1.67)	0.941
Platelets as per 1 × 106	0.98 (0.95-1.00)	0.088
Creatinine as per 1 mg/dL increase	0.01 (0.00-4.55)	0.134
Bilirubin as per 1 mg/dL increase	0.90 (0.59-1.39)	0.642
Albumin as per 1 g/L increase	0.65 (0.17-2.43)	0.521
INR as per 1 point increase	0.06 (0.00-4.39)	0.196
HVGP as per 1 mmHg increase	1.12 (0.94-1.33)	0.195
MAP as per 1 mmHg increase	1.01 (0.93-1.10)	0.791
Previous ascites	1.73 (0.34-8.96)	0.511
Previous hepatocellular carcinoma	3.41 (0.40-29.45)	0.264
Previous hepatic encephalopathy	2.72 (0.53-14.08)	0.233
No previous decompensation	0.58 (0.11-3.01)	0.518
Acute hemodynamic response	2.99 (0.36-24.91)	0.312
Chronic hemodynamic response-10%	0.23 (0.02-2.57)	0.234
Chronic hemodynamic response-20%	0.02 (0.00-427.79)	0.455

BMI: Body mass index; HVPG: Hepatic venous gradient pressure; INR: International normalized ratio; MAP: Mean arterial pressure; SBP: Spontaneous bacterial peritonitis.