Propranolol Compared with Propranolol plus Isosorbide-5-Mononitrate for Portal Hypertension in Cirrhosis A Randomized Controlled Study Joan Carles Garcia-Pagan, MD; Faust Feu, MD; Jaume Bosch, MD; and Joan Rodes, MD
Objective: To investigate whether isosorbide-5-mononitrate (Is5-Mn) given with propranolol reduces hepatic portal pressure more than does propranolol alone in patients with cirrhosis. Design: A randomized controlled trial. Patients: Fifty patients with cirrhosis and esophageal varices entered and 42 completed the study. Intervention: Twenty-one patients received oral propranolol at increasing doses until their resting heart rate was reduced by 25%, and 21 patients received oral propranolol (on the same schedule) plus oral Is-5-Mn, 40 mg twice a day. Measurements: Hepatic vein pressure gradient, liver function, and splanchnic and systemic hemodynamics before and after 3 months of continuous therapy. Main Results: At 3 months, the hepatic venous pressure gradient decreased more (P < 0.01) in patients given propranolol plus Is-5-Mn (19%, from 18.4 ± 3.9 to 14.9 ± 3.8 mm Hg; 95% CI, — 2.4 to —4.5 mm Hg) than in those given propranolol alone (10%, from 18.2 ± 3.5 to 16.3 ± 3.1 mm Hg; CI, - 1.1 to - 2.7 mm Hg). The hepatic venous pressure gradient decreased by more than 20% of the baseline value in 10% of patients receiving propranolol, but in 50% of patients receiving combined therapy (P < 0.02). There were statistically significant decreases in hepatic blood flow and the intrinsic clearance of indocyanine green after propranolol therapy, but not after combined therapy. The treatments caused similar reductions in azygos blood flow and cardiac output. Conclusions: The long-term combined administration of propranolol plus Is-5-Mn reduces portal pressure more than propranolol alone without adverse effects on hepatic perfusion and liver function. Whether this greater hemodynamic effect translates into better clinical efficacy should be determined in randomized controlled trials.
Annals of Internal Medicine. 1991;114:869-873. From the Hospital Clinic i Provincial, University of Barcelona, Barcelona, Spain. For current author addresses, see end of text.
x ropranolol has become widely used to treat portal hypertension. Many studies have shown that continuous propranolol administration reduces the risk for bleeding and rebleeding from esophageal varices in patients with cirrhosis (1-6). These beneficial effects of propranolol are thought to result from its action in decreasing portal pressure and portocollateral (azygos) blood flow (7, 8). However, the effects of propranolol on portal pressure are heterogeneous, and many patients have only a mild reduction (7, 9, 10). This finding may be clinically relevant; a recent study showed that to protect completely against variceal hemorrhage, the portal pressure gradient (evaluated as hepatic venous pressure gradient) had to be reduced to less than 12 mm Hg (11). However, such a decrease in portal pressure is achieved in only a minority of the patients. Recently, the acute administration of isosorbide-5mononitrate (Is-5-Mn), a long-acting venous dilator, has been shown to enhance the reduction in portal pressure caused by propranolol (10). However, whether this beneficial effect is maintained with long-term therapy is unknown. We examined whether chronic combined therapy with propranolol and Is-5-Mn achieves better hemodynamic effects than treatment with propranolol alone in patients with portal hypertension from liver cirrhosis.
Methods The study was a randomized trial of propranolol (n = 21) or propranolol plus Is-5-Mn (n = 21) conducted in 42 patients with cirrhosis and portal hypertension. Repeated hemodynamics studies were done before and after 3 months of continuous therapy. The patients were selected from among patients who had portal hypertension, cirrhosis, and esophageal varices; who had been referred to the Hepatic Hemodynamics Laboratory at the Liver Unit for pharmacologic therapy; who had no contraindications to treatment with propranolol or Is-5-Mn; who were not taking beta-blockers or vasodilators; and who agreed to participate in the study. Patients with insulin-dependent diabetes, hepatocellular carcinoma, tense ascites, encephalopathy, extrahepatic malignancies, or renal, cardiac, or pulmonary disease were excluded. All alcoholics said that they had abstained from alcohol for at least 1 month before entry. All patients had esophageal varices at endoscopy, 22 had previously bled from the varices, and 14 had moderately severe ascites (Table 1). The protocol was approved by the Clinical Investigation Committee of the Hospital Clinic i Provincial of Barcelona (June 1988). Patients were randomly allocated to propranolol or propranolol plus Is-5-Mn using sealed envelopes. Of the 25 patients allocated to propranolol therapy, only 21 had the scheduled follow-up examination. Patients withdrew because of variceal hemorrhage that required emergency sclerotherapy (n = 1) and noncompliance {n = 3). One of these 3 patients bled from ©1991 American College of Physicians
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Table 1. Clinical Characteristics
of the Two Treatment
Groups*
Characteristic
Propranolol Group (n = 2\)
Propranolol plus Is-5-Mn Group (n = 21)
Age, y Men:women Alcoholic:nonalcoholic Plasma bilirubin level, ixmollL(mgldL) Plasma albumin level, gIL Prothrombin ratio, % Child-Pugh score, points (range) Patients with esophageal varices, n Patients with previous variceal bleeding, n Patients with ascites, n
55 ± 10 15:6 14:7 34 ± 15 (2.0 ± 0.9) 34 ± 6.7 66 ± 12 6.9 ± 1.2 (5-9) 21 9% 6
55 ± 9 12:9 14:7 24 ± 14 (1.4 ± 0.8)t 38 ± 8.3 65 ± 15 6.3 ± 1.4 (5-9) 21 13§ 8
* Is-5-Mn = isosorbide-5-mononitrate. Plus-minus values are means ± SD. t P < 0.05. X Two patients also had ascites. § Five patients also had ascites.
varices 1 month after propranolol therapy was discontinued; on admission, hepatocellular carcinoma with portal thrombosis was detected, and he finally died. Both patients who bled from varices had previously bled. Of the 25 patients allocated to propranolol plus Is-5-Mn, 4 withdrew: 1 because of post-transfusion hepatitis causing death from fulminant liver failure, 2 because of noncompliance, and 1 because of headache. All noncompliant patients were alcoholics who resumed alcohol consumption during the study period. Hemodynamic studies were done after an overnight fast. The hepatic venous pressure, azygos blood flow, hepatic blood flow, cardiopulmonary pressures, and cardiac output were measured as previously described (7, 10). The hepatic and intrinsic clearance of indocyanine green were measured at steady state; these values were used as quantitative liver function test results (10). Portal pressure was measured as the hepatic venous pressure gradient, the difference between wedged (occluded) and free hepatic venous pressure. In one patient in the propranolol plus Is-5-Mn group, this variable could not be measured. Mean arterial pressure and heart rate were measured noninvasively using an automatic sphygmomanometer (Dinamap, Critikon, Inc., Tampa, Florida). All variables were measured at least twice during each study period. Continuous drug therapy was started after the baseline hemodynamic evaluation was completed. The propranolol group (n = 21) initially received 20 mg twice daily orally. The dosage was increased stepwise at 3-day intervals until the patient's resting heart rate was reduced by 25% or to 55 beats/min (1, 11). This dosage was maintained for the next 3 months. In the group receiving combined therapy (n = 21), oral Is-5-Mn therapy was started when the patient was receiving the maintenance dose of propranolol. The dosage of Is-5-Mn was also progressively increased, from 20 mg at bedtime to 40 mg twice daily over 2 weeks. When their condition had stabilized with therapy at their maintenance dosage, patients were seen at monthly intervals. Three months after treatment was begun, another hemodynamic study, identical to the baseline study, was conducted. Patients had fasted but had taken their usual morning medication. Follow-up visits were scheduled twice weekly for the first 4 weeks and every month thereafter. Compliance with the therapeutic regimen was assessed at each follow-up visit. At each visit, the patient's resting heart rate and arterial blood pressure were measured repeatedly over a 15-minute period to verify that the reduction in heart rate obtained during the titration period was maintained. In addition, the hemodynamic response to propranolol alone was evaluated in 12 of the 21 patients receiving propranolol plus Is-5-Mn. In 6 of these patients, the response to propranolol was evaluated during the initial (baseline) hemodynamic study by measuring the hemodynamic changes 30 minutes after an intravenous infusion of propranolol, 0.15 mg/kg body weight (10). The remaining 6 patients had two separate hemodynamic evaluations: after their conditions had stabilized with oral propranolol therapy and before the addition of Is-5-Mn to therapy 870
and then after 3 months of combination therapy with propranolol plus Is-5-Mn. No specific selection criteria were used to conduct this sequential evaluation. The results are reported as means ± standard deviation (SD). The Student f-test for paired and unpaired data and the chi-square test were used in the statistical analysis of the results. Confidence intervals (CIs) of 95% are provided where appropriate. Results The study patients had severe portal hypertension, as indicated by the presence of esophageal varices and by a markedly increased hepatic venous pressure gradient. The two groups of patients did not differ substantially in baseline clinical and hemodynamic data, except for a slightly higher plasma bilirubin level in the propranolol group (Tables 1 and 2). No difference in sex, cause of cirrhosis, Child-Pugh score, serum bilirubin level, serum albumin level, the presence of ascites, or previous variceal bleeding was found in the baseline systemic or splanchnic hemodynamic variables. Continuous combination therapy with propranolol and Is-5-Mn reduced the hepatic venous pressure gradient much more than did treatment with propranolol alone (Table 2). Whereas the hepatic venous pressure gradient decreased from 18.2 ± 3.5 to 16.3 ± 3.1 mm Hg (95% CI, - 1.1 to - 2.7 mm Hg) in the propranolol group, it decreased from 18.4 ± 3.9 to 14.9 ± 3.8 mm Hg (CI, - 2.4 to - 4.5 mm Hg) in the combination therapy group. The hepatic venous pressure gradient decreased to less than 12 mm Hg in two and four patients in the respective treatment groups (Figure 1). The hepatic venous pressure gradient decreased by more than 20% of the baseline value in 10% of patients receiving propranolol and in 50% of those receiving combined therapy; conversely, the hepatic venous pressure gradient decreased by less than 10% of the baseline value in 43% of patients treated with propranolol as compared with 20% of those treated with propranolol and Is-5-Mn (P < 0.02) (Figure 2). Among patients who received combination therapy, no significant difference was noted between patients whose hepatic venous pressure gradient markedly decreased (by more than 20%) and those whose hepatic venous pressure gradient decreased by less than 20%.
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Patients treated with propranolol alone had a decrease in hepatic blood flow (P < 0.01), in the hepatic clearance of indocyanine green (P < 0.05), and in the hepatic intrinsic clearance (P < 0.01) (Table 2). None of these adverse effects was noted in the patients receiving combined therapy (Table 2). Both treatment groups had similar reductions in azygos blood flow, cardiac output, and heart rate (Table 2). Mean arterial pressure was not modified by propranolol, but was decreased moderately by combined therapy (Table 2). Similar findings were noted in the subgroup of patients in whom sequential hemodynamic studies had been conducted. Combination therapy had further decreased their hepatic venous pressure gradient (at baseline, 18.6 ± 3.5 mm Hg; with propranolol, 16.3 ± 2.9 mm Hg [P < 0.01]; with propranolol plus Is-5-Mn, 14.9 ± 3.2 mm Hg [P < 0.01]), improved their hepatic blood flow (at baseline, 998 ± 362 mL/min; with propranolol, 793 ± 288 mL/min [P < 0.05]; with propranolol plus Is-5-Mn, 867 ±247 mL/min [P > 0.05]), and improved their hepatic intrinsic clearance (at baseline, 251 ± 133 mL/min; with propranolol, 216 ± 114 mL/ min [P < 0.05]; with propranolol plus Is-5-Mn, 271 ± 119 mL/min [P > 0.05]). These improvements were obtained without reversing the reduction of azygos blood flow (at baseline, 568 ± 237 mL/min; with propranolol, 389 ± 180 mL/min [P < 0.05]; with propranolol plus Is-5-Mn, 347 ± 111 mL/min [P > 0.05]). Six patients in the propranolol group had ascites at inclusion; ascites resolved with diuretics in four of these patients during follow-up, whereas mild ascites persisted in the other two. Two previously nonascitic patients developed ascites; in both, it was controlled with sodium restriction and espironolactone, 100 mg/d, on an outpatient basis. In the combined therapy group, eight patients had ascites at entry; ascites resolved with di-
uretic therapy in five patients during follow-up, whereas mild ascites persisted in the other three. No patient developed ascites during follow-up. Neither therapy substantially changed plasma creatinine and electrolyte levels (Table 2). Discussion The introduction of continuous pharmacologic therapy has been a major innovation in therapy for portal hypertension (8). Hemodynamic studies showing a reduction in portal pressure and in gastroesophageal collateral blood flow after the administration of propranolol provided a rationale for the use of this therapy (1, 7). It was assumed that if an increased portal pressure were responsible for the formation and rupture of the esophageal varices, a sustained reduction in portal pressure would decrease the risk for variceal hemorrhage (12). The results of recent longitudinal studies in a large series of patients with portal hypertension and cirrhosis strongly support this suggestion by showing that variceal bleeding did not occur in patients whose hepatic venous pressure gradient decreased to 12 mm Hg or less during the study period (11). Unfortunately, achieving such a decrease in portal pressure was possible in few patients (11); the portal pressure in 30% to 50% of patients decreased by less than 10% (7, 9, 10). On the other hand, propranolol decreases liver blood flow and the intrinsic clearance of indocyanine green as a measure of quantitative liver function (10, 13), changes that, albeit mild, may indicate an adverse effect in patients with advanced liver failure. Because of these limitations, other pharmacologic agents have been studied, especially the long-acting nitrates (14), calcium-channel blockers (15), and serotonin antagonists (16), but none has been shown to be supe-
Table 2. Changes in Hemodynamic Variables, Quantitative Liver Function Test Results, Plasma Creatinine Levels, and Renal Electrolyte Levels in the Two Treatment Groups* Measurement Baseline Hepatic venous pressure gradient, mm Hg Azygos blood flow, mL/min Hepatic blood flow, mL/min Mean arterial pressure, mm Hg Heart rate, beats/min Cardiac output, LImin Systemic vascular resistance, dynes per cm~5 Pulmonary artery pressure, mm Hg Pulmonary wedge pressure, mm Hg Right atrial pressure, mm Hg Intrinsic clearance of indocyanine green, mL/min Hepatic clearance of indocyanine green, mL/min Plasma creatinine level, fimol/L (mg/dL) Plasma sodium level, mmol/L Plasma potassium level, mmol/L
Propranolol Group 3 months
Propranolol plus»Is-5-Mn Group 3 months Baseline
18.2 630 1476 91 81 7.9
± ± ± ± ± ±
3.5 182 582 13 9 1.6
16.3 445 1085 88 61 6.3
± 3.It ± 129t ± 361t ± 14 ±6t ± 1.1*
18.4 605 1229 82 81 7.8
± ± ± ± ± ±
3.9 304 506 8 11 2.0
14.9 382 997 75 61 6.0
± 3.8t§ ± 163t ± 305 ±9t|| ±6t ± 1.5*
935 11.7 6.6 2.9
± ± ± ±
277 3.4 3.2 1.9
1097 13.6 8.8 4.6
± ± ± ±
872 12.5 6.7 2.2
± ± ± ±
273 3.6 3.0 2.6
1011 14.0 7.8 4.3
± ± ± ±
232 ± 98 201 88 137 4.0
± ± ± ±
305t 3.9 3.6* 2.6t
208 ± 921:
80 173 ± 35(1.0 ± 0.4) 97 ± 3.0 140 ± 0.3 4.1 ±
63t 27(1.1 ± 0.3) 1.5 0.5
302 ± 154 260 80 137 4.1
294* 4.9 2.9 2.4t
284 ± 132
± 134 242 ± ± 18 (0.9 ± 0.2) 80 ± ± 2.9 139 ± 4.3 ± ±0.3
130 18 (0.9 ± 0.2) 3.2 0.4
* Is-5-Mn = isosorbide-5-mononitrate. Data are presented as means ± SD. t P < 0.01 compared with the baseline value. t P < 0.05 compared with the baseline value. § P < 0.01 compared with the change seen in the propranolol group. || P < 0.05 compared with the change seen in the propranolol group.
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Figure 1. Individual changes in the hepatic venous pressure gradient (HVPG) after continuous therapy with propranolol or propranolol plus isosorbide-5-mononitrate (Is-5Mn). The vertical lines indicate the mean value ± SD before and after treatment. The hepatic venous pressure gradient decreased by a much greater percentage after treatment with propranolol plus Is-5-Mn than after treatment with propranolol alone (19% ± 11% compared with 10% ± 9%; P < 0.01).
rior to propranolol or suitable for prolonged therapy. A recent acute hemodynamic study from our laboratory showed that the portal pressure-reducing effect of propranolol was enhanced by Is-5-Mn, suggesting that combination therapy with these drugs may be better than therapy with either drug alone (10). Our results clearly show that long-term combination therapy with propranolol and Is-5-Mn can reduce portal pressure much more than can therapy with propranolol alone. This conclusion is evident from a comparison of the following measures: the average decrease in portal pressure (19% with combination therapy compared with 10% with single-agent therapy), the proportion of patients whose hepatic venous pressure gradient is markedly decreased (50% compared with 10%), and the proportion of patients whose gradient is reduced to less than 12 mm Hg (20% compared with 10%). Enhanced portal pressure reduction with Is-5-Mn was also noted in the subgroup of patients from whom measurements were obtained before therapy, after propranolol therapy, and after 3 months of combined therapy. In these
Figure 2. The magnitude of the reduction in the hepatic venous pressure gradient (HVPG) after long-term therapy with propranolol or propranolol plus isosorbide-5-mononitrate (/s-5-A//t). The difference in effect between the treatments was significant (P < 0.02).
872
patients, the decrease in the hepatic venous pressure gradient seen with propranolol therapy almost doubled with combination therapy. Altogether, these findings suggest that combined therapy protects patients better than does treatment with propranolol alone from the risk for variceal hemorrhage (11, 12). The mechanism by which combined therapy enhances the reduction in the hepatic venous pressure gradient is likely to be related to the vasodilatory effect of Is-5-Mn on the portal venous system (17). This hypothesis is supported by the fact that patients receiving propranolol alone or with Is-5-Mn had a similar reduction in cardiac output and azygos blood flow, suggesting that the changes in portal venous inflow were similar in both groups. In this context, the greater decrease in portal pressure found in the combined-therapy group probably resulted from a reduction in portal vascular resistance, a variable that may actually be increased by propranolol (18). In that regard, we have documented that chronic therapy with Is-5-Mn reduces portal pressure without decreasing portal blood flow and azygos blood flow, further suggesting a vasodilatory effect on the portal system in patients with cirrhosis (14). This study also showed that Is-5-Mn maintained vasodilatory effects with long-term administration; this finding is in keeping with the suggestion that Is-5-Mn, administered twice a day, is probably a nitrate that induces less tolerance and that, therefore, is more suitable than other nitrates for chronic therapy (14, 19). An additional advantage of Is-5-Mn over its parent compound, isosorbide dinitrate, is that the former has no first-pass effect, making the appropriate dosage much easier to determine in patients with cirrhosis. Unlike patients receiving propranolol, patients receiving combined therapy did not show adverse effects on liver function and hepatic blood flow; they had a similar beneficial reduction in azygos blood flow. The maintenance of liver perfusion and hepatic function represents an additional advantage of combined therapy over therapy with propranolol alone. The maintenance of hepatic blood flow probably results from a vasodilatory effect of
15 May 1991 • Annals of Internal Medicine • Volume 114 • Number 10
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Is-5-Mn on the hepatic artery, an effect that we have also documented in patients and experimental animals with cirrhotic portal hypertension receiving Is-5-Mn (14). The maintenance of hepatic perfusion is probably why combined therapy does not decrease intrinsic clearance of indocyanine green. Arterial blood pressure decreased slightly with combined therapy, but this decrease was well tolerated by all patients. No patient developed ascites during follow-up, and no changes in plasma creatinine or electrolyte levels were noted. Our results show that combination therapy with a splanchnic vasoconstrictor, propranolol, and a venous dilator, Is-5-Mn, improves the hemodynamic response to the vasoconstrictor in portal hypertension. This combination therapy is similar in several ways to that with vasopressin and nitroglycerin. Such therapy, used to treat variceal hemorrhage, was introduced after it was shown to improve hemodynamic response (20). It was subsequently confirmed to be superior to therapy with vasopressin alone in several controlled studies (21, 22). Our study results show that long-term combined treatment with propranolol and Is-5-Mn reduces portal pressure more and achieves better hepatic hemodynamic results than does treatment with propranolol alone. These data suggest that combined therapy might be preferable to therapy with propranolol alone in the pharmacologic treatment of portal hypertension. Whether the greater hemodynamic effect translates into better clinical efficacy should be objectively assessed by appropriate randomized controlled trials. Acknowledgments: The authors thank Ms. Angels Baringo for her assistance and Ms. Lidia Paris and Ms. Eulalia Ventura for secretarial support. Grant Support: In part by the Fundaci6 Catalana per a L'Estudi de les Malalties del Fetge and Fondo de Investigaciones Sanitarias de la Seguridad Social (FISS-91/0734). Dr. Garcia-Pagan held a research fellowship from the FISS (89/1516). Requests for Reprints: Jaume Bosch, MD, Hepatic Hemodynamics Laboratory, Liver Unit, Hospital Clinic i Provincial, CI. Villaroel 170, 08036 Barcelona, Spain. Current Author Addresses: Drs. Garcia-Pagan, Feu, Bosch, and Rod6s: Hepatic Hemodynamics Laboratory, Liver Unit, Hospital Clinic i Provincial, CI. Villaroel 170, 08036 Barcelona, Spain. References 1. Lebrec D, Poynard T, Hillon P, Benhamou JP. Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis. N Engl J Med. 1981;305:1371-4. 2. Pascal JP, Cales P. Propranolol in the prevention of first upper gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varices. N Engl J Med. 1987;317:856-61.
3. Bosch J, Groszmann RJ, Grace N, et al. Propranolol in the prevention of the first hemorrhage from esophageal varices: results of a randomized, double blind, cooperative clinical trial. J Hepatol. 1988;7:S12. 4. Colombo M, de Franchis R, Tommasini M, Sangiovanni A, Dioguardi N. Beta-blockade prevents recurrent gastrointestinal bleeding in well-compensated patients with alcoholic cirrhosis: a multicenter randomized controlled trial. Hepatology. 1989;9:433-8. 5. The Italian Multicenter Project for Propranolol in Prevention of Bleeding. Propranolol for prophylaxis of bleeding in cirrhotic patients with large varices: a multicenter, randomized clinical trial. Hepatology. 1988;8:1-5. 6. Pagliaro L, Burroughs AK, Sorensen TI, et al. Therapeutic controversies and randomised controlled trials: prevention of bleeding and rebleeding in cirrhosis. Gastroenterol Int. 1989;2:71-84. 7. Bosch J, Masti R, Kravetz D, et al. Effects of propranolol on azygos venous blood flow and hepatic and systemic hemodynamics in cirrhosis. Hepatology. 1984;4:1200-5. 8. Lebrec D, Corbie M, Nouel O, Benhamou JP. Propranolol—a medical treatment for portal hypertension? Lancet. 1980;2:180-2. 9. Garcia-Tsao G, Grace ND, Groszmann RJ, et al. Short-term effects of propranolol on portal venous pressure. Hepatology. 1986;6:101-6. 10. Garcia-Pagan JC, Navasa M, Bosch J, Bru C, Pizcueta P, Rodes J. Enhancement of portal pressure reduction by the association of isosorbide-5-mononitrate to propranolol administration in patients with cirrhosis. Hepatology. 1990;11:230-8. 11. Groszmann RJ, Bosch J, Grace ND, et al. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology. 1990; 99:1401-7. 12. Rigau J, Bosch J, Bordas JM, et al. Endoscopic measurement of variceal pressure in cirrhosis: correlation with portal pressure and variceal hemorrhage. Gastroenterology. 1989;96:873-80. 13. Vinel JP, Caucanas JP, Cates P, Suduca JM, Voigt JJ, Pascal JP. Effect of propranolol on metabolic activity of the liver in patients with alcoholic cirrhosis. J Hepatol. 1988;7:186-92. 14. Garcia-Pagan JC, Feu F, Navasa M, et al. Long-term haemodynamic effects of isosorbide-5-mononitrate in patients with cirrhosis and portal hypertension. J Hepatol. 1990;11:189-95. 15. Navasa M, Bosch J, Reichen J, et al. Effects of verapamil on hepatic and systemic hemodynamics and liver function in patients with cirrhosis and portal hypertension. Hepatology. 1988;8:850-4. 16. Vorobioff J, Garcia-Tsao G, Groszmann R, et al. Long-term hemodynamic effects of ketanserin, a 5-hydroxytryptamine blocker, in portal hypertensive patients. Hepatology. 1989;9:88-91. 17. Navasa M, Chesta J, Bosch J, Rodes J. Reduction of portal pressure by isosorbide 5-mononitrate in patients with cirrhosis. Gastroenterology. 1989;96:1110-8. 18. Kroeger RJ, Groszmann RJ. Increased portal venous resistance hinders portal pressure reduction during the administration of betaadrenergic blocking agents in a portal hypertensive model. Hepatology. 1985;5:97-101. 19. Abrams J. Nitrate tolerance and dependence. Am Heart J. 1980;99: 113-23. 20. Groszmann RJ, Kravetz D, Bosch J, et al. Nitroglycerin improves the hemodynamic response to vasopressin in portal hypertension. Hepatology. 1982;2:757-62. 21. Bosch J, Groszmann RJ, Garcia-Pagan JC, et al. Association of transdermal nitroglycerin to vasopressin infusion in the treatment of variceal hemorrhage: a placebo-controlled clinical trial. Hepatology. 1989;10:962-8. 22. Gimson AE, Westaby D, Hegarty J, Watson A, WilUams R. A randomized trial of vasopressin and vasopressin plus nitroglycerin in the control of acute variceal hemorrhage. Hepatology. 1986;6: 410-3.
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Objective: To investigate whether isosorbide-5-mononitrate (Is5-Mn) given with propranolol reduces hepatic portal pressure more than does propranolol alone in patients with cirrhosis. Design: A randomized controlled trial. Patients: Fifty patients with cirrhosis and esophageal varices entered and 42 completed the study. Intervention: Twenty-one patients received oral propranolol at increasing doses until their resting heart rate was reduced by 25%, and 21 patients received oral propranolol (on the same schedule) plus oral Is-5-Mn, 40 mg twice a day. Measurements: Hepatic vein pressure gradient, liver function, and splanchnic and systemic hemodynamics before and after 3 months of continuous therapy. Main Results: At 3 months, the hepatic venous pressure gradient decreased more (P < 0.01) in patients given propranolol plus Is-5-Mn (19%, from 18.4 ± 3.9 to 14.9 ± 3.8 mm Hg; 95% CI, — 2.4 to —4.5 mm Hg) than in those given propranolol alone (10%, from 18.2 ± 3.5 to 16.3 ± 3.1 mm Hg; CI, - 1.1 to - 2.7 mm Hg). The hepatic venous pressure gradient decreased by more than 20% of the baseline value in 10% of patients receiving propranolol, but in 50% of patients receiving combined therapy (P < 0.02). There were statistically significant decreases in hepatic blood flow and the intrinsic clearance of indocyanine green after propranolol therapy, but not after combined therapy. The treatments caused similar reductions in azygos blood flow and cardiac output. Conclusions: The long-term combined administration of propranolol plus Is-5-Mn reduces portal pressure more than propranolol alone without adverse effects on hepatic perfusion and liver function. Whether this greater hemodynamic effect translates into better clinical efficacy should be determined in randomized controlled trials.
Annals of Internal Medicine. 1991;114:869-873. From the Hospital Clinic i Provincial, University of Barcelona, Barcelona, Spain. For current author addresses, see end of text.
x ropranolol has become widely used to treat portal hypertension. Many studies have shown that continuous propranolol administration reduces the risk for bleeding and rebleeding from esophageal varices in patients with cirrhosis (1-6). These beneficial effects of propranolol are thought to result from its action in decreasing portal pressure and portocollateral (azygos) blood flow (7, 8). However, the effects of propranolol on portal pressure are heterogeneous, and many patients have only a mild reduction (7, 9, 10). This finding may be clinically relevant; a recent study showed that to protect completely against variceal hemorrhage, the portal pressure gradient (evaluated as hepatic venous pressure gradient) had to be reduced to less than 12 mm Hg (11). However, such a decrease in portal pressure is achieved in only a minority of the patients. Recently, the acute administration of isosorbide-5mononitrate (Is-5-Mn), a long-acting venous dilator, has been shown to enhance the reduction in portal pressure caused by propranolol (10). However, whether this beneficial effect is maintained with long-term therapy is unknown. We examined whether chronic combined therapy with propranolol and Is-5-Mn achieves better hemodynamic effects than treatment with propranolol alone in patients with portal hypertension from liver cirrhosis.
Methods The study was a randomized trial of propranolol (n = 21) or propranolol plus Is-5-Mn (n = 21) conducted in 42 patients with cirrhosis and portal hypertension. Repeated hemodynamics studies were done before and after 3 months of continuous therapy. The patients were selected from among patients who had portal hypertension, cirrhosis, and esophageal varices; who had been referred to the Hepatic Hemodynamics Laboratory at the Liver Unit for pharmacologic therapy; who had no contraindications to treatment with propranolol or Is-5-Mn; who were not taking beta-blockers or vasodilators; and who agreed to participate in the study. Patients with insulin-dependent diabetes, hepatocellular carcinoma, tense ascites, encephalopathy, extrahepatic malignancies, or renal, cardiac, or pulmonary disease were excluded. All alcoholics said that they had abstained from alcohol for at least 1 month before entry. All patients had esophageal varices at endoscopy, 22 had previously bled from the varices, and 14 had moderately severe ascites (Table 1). The protocol was approved by the Clinical Investigation Committee of the Hospital Clinic i Provincial of Barcelona (June 1988). Patients were randomly allocated to propranolol or propranolol plus Is-5-Mn using sealed envelopes. Of the 25 patients allocated to propranolol therapy, only 21 had the scheduled follow-up examination. Patients withdrew because of variceal hemorrhage that required emergency sclerotherapy (n = 1) and noncompliance {n = 3). One of these 3 patients bled from ©1991 American College of Physicians
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Table 1. Clinical Characteristics
of the Two Treatment
Groups*
Characteristic
Propranolol Group (n = 2\)
Propranolol plus Is-5-Mn Group (n = 21)
Age, y Men:women Alcoholic:nonalcoholic Plasma bilirubin level, ixmollL(mgldL) Plasma albumin level, gIL Prothrombin ratio, % Child-Pugh score, points (range) Patients with esophageal varices, n Patients with previous variceal bleeding, n Patients with ascites, n
55 ± 10 15:6 14:7 34 ± 15 (2.0 ± 0.9) 34 ± 6.7 66 ± 12 6.9 ± 1.2 (5-9) 21 9% 6
55 ± 9 12:9 14:7 24 ± 14 (1.4 ± 0.8)t 38 ± 8.3 65 ± 15 6.3 ± 1.4 (5-9) 21 13§ 8
* Is-5-Mn = isosorbide-5-mononitrate. Plus-minus values are means ± SD. t P < 0.05. X Two patients also had ascites. § Five patients also had ascites.
varices 1 month after propranolol therapy was discontinued; on admission, hepatocellular carcinoma with portal thrombosis was detected, and he finally died. Both patients who bled from varices had previously bled. Of the 25 patients allocated to propranolol plus Is-5-Mn, 4 withdrew: 1 because of post-transfusion hepatitis causing death from fulminant liver failure, 2 because of noncompliance, and 1 because of headache. All noncompliant patients were alcoholics who resumed alcohol consumption during the study period. Hemodynamic studies were done after an overnight fast. The hepatic venous pressure, azygos blood flow, hepatic blood flow, cardiopulmonary pressures, and cardiac output were measured as previously described (7, 10). The hepatic and intrinsic clearance of indocyanine green were measured at steady state; these values were used as quantitative liver function test results (10). Portal pressure was measured as the hepatic venous pressure gradient, the difference between wedged (occluded) and free hepatic venous pressure. In one patient in the propranolol plus Is-5-Mn group, this variable could not be measured. Mean arterial pressure and heart rate were measured noninvasively using an automatic sphygmomanometer (Dinamap, Critikon, Inc., Tampa, Florida). All variables were measured at least twice during each study period. Continuous drug therapy was started after the baseline hemodynamic evaluation was completed. The propranolol group (n = 21) initially received 20 mg twice daily orally. The dosage was increased stepwise at 3-day intervals until the patient's resting heart rate was reduced by 25% or to 55 beats/min (1, 11). This dosage was maintained for the next 3 months. In the group receiving combined therapy (n = 21), oral Is-5-Mn therapy was started when the patient was receiving the maintenance dose of propranolol. The dosage of Is-5-Mn was also progressively increased, from 20 mg at bedtime to 40 mg twice daily over 2 weeks. When their condition had stabilized with therapy at their maintenance dosage, patients were seen at monthly intervals. Three months after treatment was begun, another hemodynamic study, identical to the baseline study, was conducted. Patients had fasted but had taken their usual morning medication. Follow-up visits were scheduled twice weekly for the first 4 weeks and every month thereafter. Compliance with the therapeutic regimen was assessed at each follow-up visit. At each visit, the patient's resting heart rate and arterial blood pressure were measured repeatedly over a 15-minute period to verify that the reduction in heart rate obtained during the titration period was maintained. In addition, the hemodynamic response to propranolol alone was evaluated in 12 of the 21 patients receiving propranolol plus Is-5-Mn. In 6 of these patients, the response to propranolol was evaluated during the initial (baseline) hemodynamic study by measuring the hemodynamic changes 30 minutes after an intravenous infusion of propranolol, 0.15 mg/kg body weight (10). The remaining 6 patients had two separate hemodynamic evaluations: after their conditions had stabilized with oral propranolol therapy and before the addition of Is-5-Mn to therapy 870
and then after 3 months of combination therapy with propranolol plus Is-5-Mn. No specific selection criteria were used to conduct this sequential evaluation. The results are reported as means ± standard deviation (SD). The Student f-test for paired and unpaired data and the chi-square test were used in the statistical analysis of the results. Confidence intervals (CIs) of 95% are provided where appropriate. Results The study patients had severe portal hypertension, as indicated by the presence of esophageal varices and by a markedly increased hepatic venous pressure gradient. The two groups of patients did not differ substantially in baseline clinical and hemodynamic data, except for a slightly higher plasma bilirubin level in the propranolol group (Tables 1 and 2). No difference in sex, cause of cirrhosis, Child-Pugh score, serum bilirubin level, serum albumin level, the presence of ascites, or previous variceal bleeding was found in the baseline systemic or splanchnic hemodynamic variables. Continuous combination therapy with propranolol and Is-5-Mn reduced the hepatic venous pressure gradient much more than did treatment with propranolol alone (Table 2). Whereas the hepatic venous pressure gradient decreased from 18.2 ± 3.5 to 16.3 ± 3.1 mm Hg (95% CI, - 1.1 to - 2.7 mm Hg) in the propranolol group, it decreased from 18.4 ± 3.9 to 14.9 ± 3.8 mm Hg (CI, - 2.4 to - 4.5 mm Hg) in the combination therapy group. The hepatic venous pressure gradient decreased to less than 12 mm Hg in two and four patients in the respective treatment groups (Figure 1). The hepatic venous pressure gradient decreased by more than 20% of the baseline value in 10% of patients receiving propranolol and in 50% of those receiving combined therapy; conversely, the hepatic venous pressure gradient decreased by less than 10% of the baseline value in 43% of patients treated with propranolol as compared with 20% of those treated with propranolol and Is-5-Mn (P < 0.02) (Figure 2). Among patients who received combination therapy, no significant difference was noted between patients whose hepatic venous pressure gradient markedly decreased (by more than 20%) and those whose hepatic venous pressure gradient decreased by less than 20%.
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Patients treated with propranolol alone had a decrease in hepatic blood flow (P < 0.01), in the hepatic clearance of indocyanine green (P < 0.05), and in the hepatic intrinsic clearance (P < 0.01) (Table 2). None of these adverse effects was noted in the patients receiving combined therapy (Table 2). Both treatment groups had similar reductions in azygos blood flow, cardiac output, and heart rate (Table 2). Mean arterial pressure was not modified by propranolol, but was decreased moderately by combined therapy (Table 2). Similar findings were noted in the subgroup of patients in whom sequential hemodynamic studies had been conducted. Combination therapy had further decreased their hepatic venous pressure gradient (at baseline, 18.6 ± 3.5 mm Hg; with propranolol, 16.3 ± 2.9 mm Hg [P < 0.01]; with propranolol plus Is-5-Mn, 14.9 ± 3.2 mm Hg [P < 0.01]), improved their hepatic blood flow (at baseline, 998 ± 362 mL/min; with propranolol, 793 ± 288 mL/min [P < 0.05]; with propranolol plus Is-5-Mn, 867 ±247 mL/min [P > 0.05]), and improved their hepatic intrinsic clearance (at baseline, 251 ± 133 mL/min; with propranolol, 216 ± 114 mL/ min [P < 0.05]; with propranolol plus Is-5-Mn, 271 ± 119 mL/min [P > 0.05]). These improvements were obtained without reversing the reduction of azygos blood flow (at baseline, 568 ± 237 mL/min; with propranolol, 389 ± 180 mL/min [P < 0.05]; with propranolol plus Is-5-Mn, 347 ± 111 mL/min [P > 0.05]). Six patients in the propranolol group had ascites at inclusion; ascites resolved with diuretics in four of these patients during follow-up, whereas mild ascites persisted in the other two. Two previously nonascitic patients developed ascites; in both, it was controlled with sodium restriction and espironolactone, 100 mg/d, on an outpatient basis. In the combined therapy group, eight patients had ascites at entry; ascites resolved with di-
uretic therapy in five patients during follow-up, whereas mild ascites persisted in the other three. No patient developed ascites during follow-up. Neither therapy substantially changed plasma creatinine and electrolyte levels (Table 2). Discussion The introduction of continuous pharmacologic therapy has been a major innovation in therapy for portal hypertension (8). Hemodynamic studies showing a reduction in portal pressure and in gastroesophageal collateral blood flow after the administration of propranolol provided a rationale for the use of this therapy (1, 7). It was assumed that if an increased portal pressure were responsible for the formation and rupture of the esophageal varices, a sustained reduction in portal pressure would decrease the risk for variceal hemorrhage (12). The results of recent longitudinal studies in a large series of patients with portal hypertension and cirrhosis strongly support this suggestion by showing that variceal bleeding did not occur in patients whose hepatic venous pressure gradient decreased to 12 mm Hg or less during the study period (11). Unfortunately, achieving such a decrease in portal pressure was possible in few patients (11); the portal pressure in 30% to 50% of patients decreased by less than 10% (7, 9, 10). On the other hand, propranolol decreases liver blood flow and the intrinsic clearance of indocyanine green as a measure of quantitative liver function (10, 13), changes that, albeit mild, may indicate an adverse effect in patients with advanced liver failure. Because of these limitations, other pharmacologic agents have been studied, especially the long-acting nitrates (14), calcium-channel blockers (15), and serotonin antagonists (16), but none has been shown to be supe-
Table 2. Changes in Hemodynamic Variables, Quantitative Liver Function Test Results, Plasma Creatinine Levels, and Renal Electrolyte Levels in the Two Treatment Groups* Measurement Baseline Hepatic venous pressure gradient, mm Hg Azygos blood flow, mL/min Hepatic blood flow, mL/min Mean arterial pressure, mm Hg Heart rate, beats/min Cardiac output, LImin Systemic vascular resistance, dynes per cm~5 Pulmonary artery pressure, mm Hg Pulmonary wedge pressure, mm Hg Right atrial pressure, mm Hg Intrinsic clearance of indocyanine green, mL/min Hepatic clearance of indocyanine green, mL/min Plasma creatinine level, fimol/L (mg/dL) Plasma sodium level, mmol/L Plasma potassium level, mmol/L
Propranolol Group 3 months
Propranolol plus»Is-5-Mn Group 3 months Baseline
18.2 630 1476 91 81 7.9
± ± ± ± ± ±
3.5 182 582 13 9 1.6
16.3 445 1085 88 61 6.3
± 3.It ± 129t ± 361t ± 14 ±6t ± 1.1*
18.4 605 1229 82 81 7.8
± ± ± ± ± ±
3.9 304 506 8 11 2.0
14.9 382 997 75 61 6.0
± 3.8t§ ± 163t ± 305 ±9t|| ±6t ± 1.5*
935 11.7 6.6 2.9
± ± ± ±
277 3.4 3.2 1.9
1097 13.6 8.8 4.6
± ± ± ±
872 12.5 6.7 2.2
± ± ± ±
273 3.6 3.0 2.6
1011 14.0 7.8 4.3
± ± ± ±
232 ± 98 201 88 137 4.0
± ± ± ±
305t 3.9 3.6* 2.6t
208 ± 921:
80 173 ± 35(1.0 ± 0.4) 97 ± 3.0 140 ± 0.3 4.1 ±
63t 27(1.1 ± 0.3) 1.5 0.5
302 ± 154 260 80 137 4.1
294* 4.9 2.9 2.4t
284 ± 132
± 134 242 ± ± 18 (0.9 ± 0.2) 80 ± ± 2.9 139 ± 4.3 ± ±0.3
130 18 (0.9 ± 0.2) 3.2 0.4
* Is-5-Mn = isosorbide-5-mononitrate. Data are presented as means ± SD. t P < 0.01 compared with the baseline value. t P < 0.05 compared with the baseline value. § P < 0.01 compared with the change seen in the propranolol group. || P < 0.05 compared with the change seen in the propranolol group.
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Figure 1. Individual changes in the hepatic venous pressure gradient (HVPG) after continuous therapy with propranolol or propranolol plus isosorbide-5-mononitrate (Is-5Mn). The vertical lines indicate the mean value ± SD before and after treatment. The hepatic venous pressure gradient decreased by a much greater percentage after treatment with propranolol plus Is-5-Mn than after treatment with propranolol alone (19% ± 11% compared with 10% ± 9%; P < 0.01).
rior to propranolol or suitable for prolonged therapy. A recent acute hemodynamic study from our laboratory showed that the portal pressure-reducing effect of propranolol was enhanced by Is-5-Mn, suggesting that combination therapy with these drugs may be better than therapy with either drug alone (10). Our results clearly show that long-term combination therapy with propranolol and Is-5-Mn can reduce portal pressure much more than can therapy with propranolol alone. This conclusion is evident from a comparison of the following measures: the average decrease in portal pressure (19% with combination therapy compared with 10% with single-agent therapy), the proportion of patients whose hepatic venous pressure gradient is markedly decreased (50% compared with 10%), and the proportion of patients whose gradient is reduced to less than 12 mm Hg (20% compared with 10%). Enhanced portal pressure reduction with Is-5-Mn was also noted in the subgroup of patients from whom measurements were obtained before therapy, after propranolol therapy, and after 3 months of combined therapy. In these
Figure 2. The magnitude of the reduction in the hepatic venous pressure gradient (HVPG) after long-term therapy with propranolol or propranolol plus isosorbide-5-mononitrate (/s-5-A//t). The difference in effect between the treatments was significant (P < 0.02).
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patients, the decrease in the hepatic venous pressure gradient seen with propranolol therapy almost doubled with combination therapy. Altogether, these findings suggest that combined therapy protects patients better than does treatment with propranolol alone from the risk for variceal hemorrhage (11, 12). The mechanism by which combined therapy enhances the reduction in the hepatic venous pressure gradient is likely to be related to the vasodilatory effect of Is-5-Mn on the portal venous system (17). This hypothesis is supported by the fact that patients receiving propranolol alone or with Is-5-Mn had a similar reduction in cardiac output and azygos blood flow, suggesting that the changes in portal venous inflow were similar in both groups. In this context, the greater decrease in portal pressure found in the combined-therapy group probably resulted from a reduction in portal vascular resistance, a variable that may actually be increased by propranolol (18). In that regard, we have documented that chronic therapy with Is-5-Mn reduces portal pressure without decreasing portal blood flow and azygos blood flow, further suggesting a vasodilatory effect on the portal system in patients with cirrhosis (14). This study also showed that Is-5-Mn maintained vasodilatory effects with long-term administration; this finding is in keeping with the suggestion that Is-5-Mn, administered twice a day, is probably a nitrate that induces less tolerance and that, therefore, is more suitable than other nitrates for chronic therapy (14, 19). An additional advantage of Is-5-Mn over its parent compound, isosorbide dinitrate, is that the former has no first-pass effect, making the appropriate dosage much easier to determine in patients with cirrhosis. Unlike patients receiving propranolol, patients receiving combined therapy did not show adverse effects on liver function and hepatic blood flow; they had a similar beneficial reduction in azygos blood flow. The maintenance of liver perfusion and hepatic function represents an additional advantage of combined therapy over therapy with propranolol alone. The maintenance of hepatic blood flow probably results from a vasodilatory effect of
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Is-5-Mn on the hepatic artery, an effect that we have also documented in patients and experimental animals with cirrhotic portal hypertension receiving Is-5-Mn (14). The maintenance of hepatic perfusion is probably why combined therapy does not decrease intrinsic clearance of indocyanine green. Arterial blood pressure decreased slightly with combined therapy, but this decrease was well tolerated by all patients. No patient developed ascites during follow-up, and no changes in plasma creatinine or electrolyte levels were noted. Our results show that combination therapy with a splanchnic vasoconstrictor, propranolol, and a venous dilator, Is-5-Mn, improves the hemodynamic response to the vasoconstrictor in portal hypertension. This combination therapy is similar in several ways to that with vasopressin and nitroglycerin. Such therapy, used to treat variceal hemorrhage, was introduced after it was shown to improve hemodynamic response (20). It was subsequently confirmed to be superior to therapy with vasopressin alone in several controlled studies (21, 22). Our study results show that long-term combined treatment with propranolol and Is-5-Mn reduces portal pressure more and achieves better hepatic hemodynamic results than does treatment with propranolol alone. These data suggest that combined therapy might be preferable to therapy with propranolol alone in the pharmacologic treatment of portal hypertension. Whether the greater hemodynamic effect translates into better clinical efficacy should be objectively assessed by appropriate randomized controlled trials. Acknowledgments: The authors thank Ms. Angels Baringo for her assistance and Ms. Lidia Paris and Ms. Eulalia Ventura for secretarial support. Grant Support: In part by the Fundaci6 Catalana per a L'Estudi de les Malalties del Fetge and Fondo de Investigaciones Sanitarias de la Seguridad Social (FISS-91/0734). Dr. Garcia-Pagan held a research fellowship from the FISS (89/1516). Requests for Reprints: Jaume Bosch, MD, Hepatic Hemodynamics Laboratory, Liver Unit, Hospital Clinic i Provincial, CI. Villaroel 170, 08036 Barcelona, Spain. Current Author Addresses: Drs. Garcia-Pagan, Feu, Bosch, and Rod6s: Hepatic Hemodynamics Laboratory, Liver Unit, Hospital Clinic i Provincial, CI. Villaroel 170, 08036 Barcelona, Spain. References 1. Lebrec D, Poynard T, Hillon P, Benhamou JP. Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis. N Engl J Med. 1981;305:1371-4. 2. Pascal JP, Cales P. Propranolol in the prevention of first upper gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varices. N Engl J Med. 1987;317:856-61.
3. Bosch J, Groszmann RJ, Grace N, et al. Propranolol in the prevention of the first hemorrhage from esophageal varices: results of a randomized, double blind, cooperative clinical trial. J Hepatol. 1988;7:S12. 4. Colombo M, de Franchis R, Tommasini M, Sangiovanni A, Dioguardi N. Beta-blockade prevents recurrent gastrointestinal bleeding in well-compensated patients with alcoholic cirrhosis: a multicenter randomized controlled trial. Hepatology. 1989;9:433-8. 5. The Italian Multicenter Project for Propranolol in Prevention of Bleeding. Propranolol for prophylaxis of bleeding in cirrhotic patients with large varices: a multicenter, randomized clinical trial. Hepatology. 1988;8:1-5. 6. Pagliaro L, Burroughs AK, Sorensen TI, et al. Therapeutic controversies and randomised controlled trials: prevention of bleeding and rebleeding in cirrhosis. Gastroenterol Int. 1989;2:71-84. 7. Bosch J, Masti R, Kravetz D, et al. Effects of propranolol on azygos venous blood flow and hepatic and systemic hemodynamics in cirrhosis. Hepatology. 1984;4:1200-5. 8. Lebrec D, Corbie M, Nouel O, Benhamou JP. Propranolol—a medical treatment for portal hypertension? Lancet. 1980;2:180-2. 9. Garcia-Tsao G, Grace ND, Groszmann RJ, et al. Short-term effects of propranolol on portal venous pressure. Hepatology. 1986;6:101-6. 10. Garcia-Pagan JC, Navasa M, Bosch J, Bru C, Pizcueta P, Rodes J. Enhancement of portal pressure reduction by the association of isosorbide-5-mononitrate to propranolol administration in patients with cirrhosis. Hepatology. 1990;11:230-8. 11. Groszmann RJ, Bosch J, Grace ND, et al. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology. 1990; 99:1401-7. 12. Rigau J, Bosch J, Bordas JM, et al. Endoscopic measurement of variceal pressure in cirrhosis: correlation with portal pressure and variceal hemorrhage. Gastroenterology. 1989;96:873-80. 13. Vinel JP, Caucanas JP, Cates P, Suduca JM, Voigt JJ, Pascal JP. Effect of propranolol on metabolic activity of the liver in patients with alcoholic cirrhosis. J Hepatol. 1988;7:186-92. 14. Garcia-Pagan JC, Feu F, Navasa M, et al. Long-term haemodynamic effects of isosorbide-5-mononitrate in patients with cirrhosis and portal hypertension. J Hepatol. 1990;11:189-95. 15. Navasa M, Bosch J, Reichen J, et al. Effects of verapamil on hepatic and systemic hemodynamics and liver function in patients with cirrhosis and portal hypertension. Hepatology. 1988;8:850-4. 16. Vorobioff J, Garcia-Tsao G, Groszmann R, et al. Long-term hemodynamic effects of ketanserin, a 5-hydroxytryptamine blocker, in portal hypertensive patients. Hepatology. 1989;9:88-91. 17. Navasa M, Chesta J, Bosch J, Rodes J. Reduction of portal pressure by isosorbide 5-mononitrate in patients with cirrhosis. Gastroenterology. 1989;96:1110-8. 18. Kroeger RJ, Groszmann RJ. Increased portal venous resistance hinders portal pressure reduction during the administration of betaadrenergic blocking agents in a portal hypertensive model. Hepatology. 1985;5:97-101. 19. Abrams J. Nitrate tolerance and dependence. Am Heart J. 1980;99: 113-23. 20. Groszmann RJ, Kravetz D, Bosch J, et al. Nitroglycerin improves the hemodynamic response to vasopressin in portal hypertension. Hepatology. 1982;2:757-62. 21. Bosch J, Groszmann RJ, Garcia-Pagan JC, et al. Association of transdermal nitroglycerin to vasopressin infusion in the treatment of variceal hemorrhage: a placebo-controlled clinical trial. Hepatology. 1989;10:962-8. 22. Gimson AE, Westaby D, Hegarty J, Watson A, WilUams R. A randomized trial of vasopressin and vasopressin plus nitroglycerin in the control of acute variceal hemorrhage. Hepatology. 1986;6: 410-3.
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