Hemodynamic effects of renin-angiotensin-aldosterone inhibitor and β-blocker combination therapy vs. β-blocker monotherapy for portal hypertension in cirrhosis: A meta-analysis

Wang,Jianrong; Lu,Wenxia; Li,Jingjing; Zhang,Rong; Zhou,Yuqing; Yin,Qin; Zheng,Yuanyuan; Wang,Fan; Xia,Yujing; Chen,Kan; Li,Sainan; Liu,Tong; Lu,Jie; Zhou,Yingqun; Guo,Chuan‑Yong

doi:10.3892/etm.2017.4210

Hemodynamic effects of renin-angiotensin-aldosterone inhibitor and β-blocker combination therapy vs. β-blocker monotherapy for portal hypertension in cirrhosis: A meta-analysis

Authors:
- Jianrong Wang
- Wenxia Lu
- Jingjing Li
- Rong Zhang
- Yuqing Zhou
- Qin Yin
- Yuanyuan Zheng
- Fan Wang
- Yujing Xia
- Kan Chen
- Sainan Li
- Tong Liu
- Jie Lu
- Yingqun Zhou
- Chuan‑Yong Guo
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Affiliations: Department of Gastroenterology, Nanjing Jiangbei People's Hospital Affiliated to Nantong University, Nanjing, Jiangsu 210048, P.R. China, The First Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China, Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China, Department of Gastroenterology, Shanghai Tenth People's Hospital, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
Published online on: March 9, 2017 https://doi.org/10.3892/etm.2017.4210
Pages: 1977-1985

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Abstract

β-blockers are commonly used for the treatment of acute variceal bleeding in cirrhosis. Renin-angiotensin-aldosterone antagonists (angiotensin I-converting enzyme inhibitors, angiotensin receptor blockers and aldosterone antagonists) are potential therapies for portal hypertension. Several studies have compared the renin-angiotensin-aldosterone system (RAAS) inhibitor and β‑blocker combination therapy vs. β-blocker monotherapy, with inconsistent results. The aim of the present study was to assess the efficacy of the RAAS inhibitor and β‑blocker combination therapy vs. β‑blocker monotherapy for hepatic vein pressure gradient (HVPG) reduction in cirrhosis. Studies were obtained using PubMed, Embase, Medline and Cochrane library databases up to July 2015, and the weighted mean difference (WMD) in HVPG reduction was used as a measure of treatment efficacy. In total, three studies (91 patients) were included. When compared to the β‑blocker monotherapy, the RAAS inhibitor and β‑blocker combination therapy resulted in a significant HVPG reduction [WMD 1.70; 95% confidence interval (CI): 0.52‑2.88]. However, there was no significant difference in the heart rate reduction between the monotherapy and combination therapy groups (WMD ‑0.11; 95% CI: ‑3.51‑3.29). In addition, no significant difference in the hemodynamic response was observed between the two groups (WMD 1.46; 95% CI: 0.93‑2.30). In conclusion, the RAAS inhibitor and β‑blocker combination therapy reduces portal hypertension significantly and to a greater extent than β‑blocker monotherapy. Both therapies reduced the heart rate to similar levels; however, the RAAS inhibitor and β‑blocker combination therapy reduced the mean arterial pressure to a greater extent. Due to the limited number of studies included, the data available do not allow a satisfactory comparison of adverse events. Moreover, further larger‑scale trials are required in order to strengthen the results of the present study.

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1	Feu F, García-Pagín JC, Bosch J, Luca A, Terés J, Escorsell A and Rodés J: Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis. Lancet. 346:1056–1059. 1995. View Article : Google Scholar : PubMed/NCBI
2	Groszmann RJ, Bosch J, Grace ND, Conn HO, Garcia-Tsao G, Navasa M, Alberts J, Rodes J, Fischer R, Bermann M, et al: Haemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology. 99:1401–1407. 1990. View Article : Google Scholar : PubMed/NCBI
3	Garcia-Tsao G and Bosch J: Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med. 362:823–832. 2010. View Article : Google Scholar : PubMed/NCBI
4	Bataller R, Ginès P, Nicolás JM, Görbig MN, Garcia-Ramallo E, Gasull X, Bosch J, Arroyo V and Rodés J: Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology. 118:1149–1156. 2000. View Article : Google Scholar : PubMed/NCBI
5	Garcia-Pagán JC, Salmerón JM, Feu F, Luca A, Ginés P, Pizcueta P, Claria J, Piera C, Arroyo V, Bosch J, et al: Effects of low-sodium diet and spironolactone on portal pressure in patients with compensated cirrhosis. Hepatology. 19:1095–1099. 1994. View Article : Google Scholar : PubMed/NCBI
6	Sowers JR, Whaley-Connell A and Epstein M: Narrative review: The emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. Ann Intern Med. 150:776–783. 2009. View Article : Google Scholar : PubMed/NCBI
7	Tandon P, Abraldes JG, Berzigotti A, Garcia-Pagan JC and Bosch J: Renin-angiotensin-aldosterone inhibitors in the reduction of portal pressure: A systematic review and meta-analysis. J Hepatol. 53:273–282. 2010. View Article : Google Scholar : PubMed/NCBI
8	De BK, Dutta D, Som R, Biswas PK, Pal SK and Biswas A: Haemodynamic effects of propranolol with spironolactone in patients with variceal bleeds: A randomized controlled trial. World J Gastroenterol. 14:1908–1913. 2008. View Article : Google Scholar : PubMed/NCBI
9	Schepke M, Wiest R, Flacke S, Heller J, Stoffel-Wagner B, Herold T, Ghauri M and Sauerbruch T: Irbesartan plus low-dose propranolol versus low-dose propranolol alone in cirrhosis: A placebo-controlled, double-blind study. Am J Gastroenterol. 103:1152–1158. 2008. View Article : Google Scholar : PubMed/NCBI
10	Abecasis R, Kravetz D, Fassio E, Ameigeiras B, Garcia D, Isla R, Landeira G, Dominguez N, Romero G, Argonz J and Terg R: Nadolol plus spironolactone in the prophylaxis of first variceal bleed in nonascitic cirrhotic patients: A preliminary study. Hepatology. 37:359–365. 2003. View Article : Google Scholar : PubMed/NCBI
11	Zhang H, Yang J, Zhu R, Zheng Y, Zhou Y, Dai W, Wang F, Chen K, Li J, Wang C, et al: Combination therapy of ursodeoxycholic acid and budesonide for PBC-AIH overlap syndrome: A meta-analysis. Drug Des Devel Ther. 9:567–574. 2015.PubMed/NCBI
12	Zhang Y, Li S, He L, Wang F, Chen K, Li J, Liu T, Zheng Y, Wang J, Lu W, et al: Combination therapy of fenofibrate and ursodeoxycholic acid in patients with primary biliary cirrhosis who respond incompletely to UDCA monotherapy: A meta-analysis. Drug Des Devel Ther. 9:2757–2766. 2015.PubMed/NCBI
13	Kjaergard LL, Villumsen J and Gluud C: Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med. 135:982–989. 2001. View Article : Google Scholar : PubMed/NCBI
14	Gluud LL: Bias in clinical intervention research. Am J Epidemiol. 163:493–501. 2006. View Article : Google Scholar : PubMed/NCBI
15	Higgins JP, Thompson SG, Deeks JJ and Altman DG: Measuring inconsistency in meta-analyses. BMJ. 327:557–560. 2003. View Article : Google Scholar : PubMed/NCBI
16	Sen S, De BK, Biswas PK, Biswas J, Das D and Maity AK: Haemodynamic effect of spironolactone in liver cirrhosis and propranolol-resistant portal hypertension. Indian J Gastroenterol. 21:145–148. 2002.PubMed/NCBI
17	Winkler C, Hobolth L, Krag A, Bendtsen F and Møller S: Effects of treatment with β-blocker and aldosterone antagonist on central and peripheral haemodynamics and oxygenation in cirrhosis. Eur J Gastroenterol Hepatol. 23:334–342. 2011. View Article : Google Scholar : PubMed/NCBI
18	De BK, Bandyopadhyay K, Das TK, Das D, Biswas PK, Majumdar D, Mandal SK, Ray S and Dasgupta S: Portal pressure response to losartan compared with propranolol in patients with cirrhosis. Am J Gastroenterol. 98:1371–1376. 2003. View Article : Google Scholar : PubMed/NCBI
19	Castano G, Viudez P, Riccitelli M and Sookoian S: A randomized study of losartan vs propranolol: Effects on hepatic and systemic haemodynamics in cirrhotic patients. Ann Hepatol. 2:36–40. 2003.PubMed/NCBI
20	Agasti AK, Mahajan AU, Phadke AY, Nathani PJ and Sawant P: Comparative randomized study on efficacy of losartan versus propranolol in lowering portal pressure in decompensated chronic liver disease. J Dig Dis. 14:266–271. 2013. View Article : Google Scholar : PubMed/NCBI
21	Debernardi-Venon W, Martini S, Biasi F, Vizio B, Termine A, Poli G, Brunello F, Alessandria C, Bonardi R, Saracco G, et al: AT1 receptor antagonist Candesartan in selected cirrhotic patients: Effect on portal pressure and liver fibrosis markers. J Hepatol. 46:1026–1033. 2007. View Article : Google Scholar : PubMed/NCBI
22	Gonzalez-Abraldes J, Albillos A, Bañares R, Del Arbol LR, Moitinho E, Rodríguez C, González M, Escorsell A, García-Pagán JC and Bosch J: Randomized comparison of long-term losartan versus propranolol in lowering portal pressure in cirrhosis. Gastroenterology. 121:382–388. 2001. View Article : Google Scholar : PubMed/NCBI
23	Venon WD, Baronio M, Leone N, Rolfo E, Fadda M, Barletti C, Todros L, Saracco G and Rizzetto M: Effects of long-term Irbesartan in reducing portal pressure in cirrhotic patients: Comparison with propranolol in a randomised controlled study. J Hepatol. 38:455–460. 2003. View Article : Google Scholar : PubMed/NCBI
24	Nevens F, Lijnen P, VanBilloen H and Fevery J: The effect of long-term treatment with spironolactone on variceal pressure in patients with portal hypertension without ascites. Hepatology. 23:1047–1052. 1996. View Article : Google Scholar : PubMed/NCBI
25	Vilas-Boas WW, Ribeiro-Oliveira A Jr, Rda Ribeiro C, Vieira RL, Almeida J, Nadu AP, Simões e Silva AC and Santos RA: Effect of propranolol on the splanchnic and peripheral renin angiotensin system in cirrhotic patients. World J Gastroenterol. 14:6824–6830. 2008. View Article : Google Scholar : PubMed/NCBI
26	Pagliaro L: Lebrec D, Poynard T, Hillon P, Benhamou J-P. Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis. A controlled study [N Engl J Med 1981;305:1371-1374]. J Hepatol. 36:148–150. 2002. View Article : Google Scholar : PubMed/NCBI
27	Shah HA, Azam Z, Rauf J, Abid S, Hamid S, Jafri W, Khalid A, Ismail FW, Parkash O, Subhan A and Munir SM: Carvedilol vs. esophageal variceal band ligation in the primary prophylaxis of variceal hemorrhage: A multicentre randomized controlled trial. J Hepatol. 60:757–764. 2014. View Article : Google Scholar : PubMed/NCBI
28	Lazebnik LB, Mikheeva OM, Toporkov AS, Komissarenko IA, Vasnev OS and Fedulenkova LV: Correction of portal hypertension by beta-adrenoblockers (atenolol and metoprolol) and inhibitors of ACE (lisinopril and enalapril) in liver cirrhosis. Eksp Klin Gastroenterol. 57–66. 2007.PubMed/NCBI
29	Wagatsuma Y, Naritaka Y, Shimakawa T, Kanako H, Keiichiro I, Shunichi S, Konno S, Katsube T and Ogawa K: Clinical usefulness of the angiotensin II receptor antagonist losartan in patients with portal hypertensive gastropathy. Hepatogastroenterology. 53:171–174. 2006.PubMed/NCBI
30	Baik SK, Park DH, Kim MY, Choi YJ, Kim HS, Lee DK, Kwon SO, Kim YJ, Park JW and Chang SJ: Captopril reduces portal pressure effectively in portal hypertensive patients with low portal venous velocity. J Gastroenterol. 38:1150–1154. 2003. View Article : Google Scholar : PubMed/NCBI
31	Klein CG: Medicinal influence on portal vein haemodynamics by cirrhosis of the liver-comparison between angiotensin II receptor antagonists and β-blockers in combination with spironolactone. J Zeitschrift fur Gastroenterologie. 39:6692001.
32	Alessandria C, Elia C, Mezzabotta L, Risso A, Andrealli A, Spandre M, Morgando A, Marzano A and Rizzetto M: Prevention of paracentesis-induced circulatory dysfunction in cirrhosis: Standard vs half albumin doses. A prospective, randomized, unblinded pilot study. Dig Liver Dis. 43:881–886. 2011.PubMed/NCBI
33	Block JP: Rifaximin improves the treatment of hepatic encephalopathy. J Clin Outcomes Manage. 17:202–204. 2010.
34	Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, Sigal S, Sheikh MY, Beavers K, Frederick T, et al: Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 362:1071–1081. 2010. View Article : Google Scholar : PubMed/NCBI
35	Van den Velde S, Nevens F, Van hee P, van Steenberghe D and Quirynen M: GC-MS analysis of breath odor compounds in liver patients. J Chromatogr B Analyt Technol Biomed Life Sci. 875:344–348. 2008. View Article : Google Scholar : PubMed/NCBI
36	Hsien L, Breddemann A, Frobel AK, Heusch A, Schmidt KG and Läer S: Off-label drug use among hospitalised children: Identifying areas with the highest need for research. Pharm World Sci. 30:497–502. 2008. View Article : Google Scholar : PubMed/NCBI
37	Revill P, Serradell N, Bolós J and Bayes M: Satavaptan. Drug Fut. 32:26–36. 2007. View Article : Google Scholar
38	Merkel C: Nonselective beta-blockers plus nitrates in portal hypertension: An open question. Hepatology. 37:1254–1256. 2003. View Article : Google Scholar : PubMed/NCBI
39	Merkel C, Sacerdoti D, Bolognesi M, et al: Pharmacological associations in the primary/prophylaxis of variceal bleeding in cirrhosis. Giornale Italiano di Endoscopia Digestiva. 21:1–5. 1998.
40	Fox K, Ford I, Steg PG, Tardif JC, Tendera M and Ferrari R: SIGNIFY Investigators: Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med. 371:1091–1099. 2014. View Article : Google Scholar : PubMed/NCBI
41	Rupnik Trošt A, Pajek J, Guček A, Osredkar J, Kovač D, Bren A, Klančič D, Saksida S, Rus I, Globokar M, et al: Influence of renin-angiotensin-aldosterone system-blocking drugs on peritoneal membrane in peritoneal dialysis patients. Ther Apher Dial. 17:425–430. 2013. View Article : Google Scholar : PubMed/NCBI
42	Fallahzadeh MK, Dormanesh B, Sagheb MM, Roozbeh J, Vessal G, Pakfetrat M, Daneshbod Y, Kamali-Sarvestani E and Lankarani KB: Effect of addition of silymarin to renin-angiotensin system inhibitors on proteinuria in type 2 diabetic patients with overt nephropathy: A randomized, double-blind, placebo-controlled trial. Am J Kidney Dis. 60:896–903. 2012. View Article : Google Scholar : PubMed/NCBI
43	Kosmala W, Przewlocka-Kosmala M, Szczepanik-Osadnik H, Mysiak A, O'Moore-Sullivan T and Marwick TH: A randomized study of the beneficial effects of aldosterone antagonism on LV function, structure, and fibrosis markers in metabolic syndrome. JACC Cardiovasc Imaging. 4:1239–1249. 2011. View Article : Google Scholar : PubMed/NCBI
44	Spinar J, Vitovec J and Spinarová L: Zastoupení resitelů studie FARIM: FARIM-FARmakoterapie po Infarktu Myokardu (Post-Myocardial Infarction Pharmacotherapy Study). Vnitrni lekarstvi. 57:778–784. 2011.(In Czech). PubMed/NCBI
45	Guney I, Selcuk NY, Altintepe L, Atalay H, Başarali MK and Büyükbaş S: Antifibrotic effects of aldosterone receptor blocker (spironolactone) in patients with chronic kidney disease. Ren Fail. 31:779–784. 2009. View Article : Google Scholar : PubMed/NCBI
46	Tylicki L, Renke M, Rutkowski P, Larczyński W, Aleksandrowicz E, Lysiak-Szydlowska W and Rutkowski B: Dual blockade of the renin-angiotensin-aldosterone system with high-dose angiotensin-converting enzyme inhibitor for nephroprotection: An open, controlled, randomized study. Scand J Urol Nephrol. 42:381–388. 2008. View Article : Google Scholar : PubMed/NCBI
47	Tylicki L, Rutkowski P, Renke M, Larczyński W, Aleksandrowicz E, Lysiak-Szydlowska W and Rutkowski B: Triple pharmacological blockade of the renin-angiotensin-aldosterone system in nondiabetic CKD: An open-label crossover randomized controlled trial. Am J Kidney Dis. 52:486–493. 2008. View Article : Google Scholar : PubMed/NCBI
48	Muller-Brunotte R, Kahan T, López B, Edner M, González A, Díez J and Malmqvist K: Myocardial fibrosis and diastolic dysfunction in patients with hypertension: Results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA). J Hypertens. 25:1958–1966. 2007. View Article : Google Scholar : PubMed/NCBI
49	Orea-Tejeda A, Colín-Ramírez E, Castillo-Martínez L, Asensio-Lafuente E, Corzo-León D, González-Toledo R, Rebollar-González V, Narváez-David R and Dorantes-García J: Aldosterone receptor antagonists induce favorable cardiac remodeling in diastolic heart failure patients. Rev Invest Clin. 59:103–107. 2007.PubMed/NCBI
50	Cavallari LH, Momary KM, Groo VL, Viana MA, Camp JR and Stamos TD: Association of beta-blocker dose with serum procollagen concentrations and cardiac response to spironolactone in patients with heart failure. Pharmacotherapy. 27:801–812. 2007. View Article : Google Scholar : PubMed/NCBI
51	Tylicki L, Biedunkiewicz B, Chamienia A, Wojnarowski K, Zdrojewski Z, Aleksandrowicz E, Lysiak-Szydlowska W and Rutkowski B: Renal allograft protection with angiotensin II type 1 receptor antagonists. Am J Transplant. 7:243–248. 2007. View Article : Google Scholar : PubMed/NCBI
52	Christensen MK, Olsen MH, Wachtell K, Tuxen C, Fossum E, Bang LE, Wiinberg N, Devereux RB, Kjeldsen SE, Hildebrandt P, et al: Does long-term losartan- vs atenolol-based antihypertensive treatment influence collagen markers differently in hypertensive patients? A LIFE substudy. Blood Press. 15:198–206. 2006. View Article : Google Scholar : PubMed/NCBI
53	Ciulla MM, Paliotti R, Esposito A, Dìez J, López B, Dahlöf B, Nicholls MG, Smith RD, Gilles L, Magrini F and Zanchetti A: Different effects of antihypertensive therapies based on losartan or atenolol on ultrasound and biochemical markers of myocardial fibrosis: Results of a randomized trial. Circulation. 110:552–557. 2004. View Article : Google Scholar : PubMed/NCBI
54	Hallberg P, Lind L, Billberger K, Michaelsson K, Karlsson J, Kurland L, Kahan T, Malmqvist K, Ohman KP, Nyström F, et al: Transforming growth factor beta1 genotype and change in left ventricular mass during antihypertensive treatment-results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA). Clin Cardiol. 27:169–173. 2004. View Article : Google Scholar : PubMed/NCBI
55	el-Agroudy AE, Hassan NA, Foda MA, Ismail AM, el-Sawy EA, Mousa O and Ghoneim MA: Effect of angiotensin II receptor blocker on plasma levels of TGF-beta 1 and interstitial fibrosis in hypertensive kidney transplant patients. Am J Nephrol. 23:300–306. 2003. View Article : Google Scholar : PubMed/NCBI
56	Hayashi M, Tsutamoto T, Wada A, Tsutsui T, Ishii C, Ohno K, Fujii M, Taniguchi A, Hamatani T, Nozato Y, et al: Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents post-infarct left ventricular remodeling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterior acute myocardial infarction. Circulation. 107:2559–2565. 2003. View Article : Google Scholar : PubMed/NCBI
57	Yang YY, Lin HC, Lee WP, Chu CJ, Lin MW, Lee FY, Hou MC, Jap JS and Lee SD: Association of the G-protein and α2-adrenergic receptor gene and plasma norepinephrine level with clonidine improvement of the effects of diuretics in patients with cirrhosis with refractory ascites: A randomised clinical trial. Gut. 59:1545–1553. 2010. View Article : Google Scholar : PubMed/NCBI
58	Ljubicić N, Bilić A and Plavsić V: Effect of propranolol on urinary prostaglandin E2 excretion and renal interlobar arterial blood flow after furosemide administration in patients with hepatic cirrhosis. Eur J Clin Pharmacol. 43:555–558. 1992. View Article : Google Scholar : PubMed/NCBI
59	Mikheeva OM, Drozdov VN and Komisarenko IA: Pharmacokinetic and pharmacodynamic characteristics of antihypertensive drugs in the treatment of hypertensive patients with chronic diseases of the liver. Ter Arkh. 83:49–55. 2011.PubMed/NCBI
60	Mikheeva OM: Pharmacokinetic and pharmacodynamic features of hypertensive drugs in treatment of patients with arterial hypertension associated with liver disease. Eksp Klin Gastroenterol. 95–101. 2010.(In Russian). PubMed/NCBI
61	Nevens F: Non-invasive variceal pressure measurements: Validation and clinical implications. Verh K Acad Geneeskd Belg. 58:413–437. 1996.PubMed/NCBI
62	Talwalkar JA and Kamath PS: Influence of recent advances in medical management on clinical outcomes of cirrhosis. Mayo Clin Proc. 80:1501–1508. 2005. View Article : Google Scholar : PubMed/NCBI
63	Yang JD and Kim WR: Surveillance for hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol. 10:16–21. 2012. View Article : Google Scholar : PubMed/NCBI
64	Lubel JS, Herath CB, Burrell LM and Angus PW: Liver disease and the renin-angiotensin system: Recent discoveries and clinical implications. J Gastroenterol Hepatol. 23:1327–1338. 2008. View Article : Google Scholar : PubMed/NCBI
65	Albillos A: Preventing first variceal hemorrhage in cirrhosis. J Clin Gastroenterol. 41:(Suppl 3). S305–S311. 2007. View Article : Google Scholar : PubMed/NCBI
66	Garcia-Tsao G, Sanyal AJ, Grace ND and Carey W: Practice Guidelines Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology: Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology. 46:922–938. 2007. View Article : Google Scholar : PubMed/NCBI
67	Samonakis DN, Triantos CK, Thalheimer U, Patch DW and Burroughs AK: Management of portal hypertension. Postgrad Med J. 80:634–641. 2004. View Article : Google Scholar : PubMed/NCBI
68	D'Amico G: The role of vasoactive drugs in the treatment of oesophageal varices. Expert Opin Pharmacother. 5:349–360. 2004. View Article : Google Scholar : PubMed/NCBI
69	Rosado B and Kamath PS: Transjugular intrahepatic portosystemic shunts: An update. Liver Transpl. 9:207–217. 2003. View Article : Google Scholar : PubMed/NCBI
70	Bosch J: The sixth Carlos E. Rubio memorial lecture. Prevention and treatment of variceal hemorrhage. P R Health Sci J. 19:57–67. 2000.PubMed/NCBI
71	Patch D and Burroughs AK: Pharmacological treatment of portal hypertension. Prog Liver Dis. 13:269–292. 1995.PubMed/NCBI
72	D'Amico G, Pagliaro L and Bosch J: The treatment of portal hypertension: A meta-analytic review. Hepatology. 22:332–354. 1995. View Article : Google Scholar : PubMed/NCBI
73	Forns X, Ginès A, Ginès P and Arroyo V: Management of ascites and renal failure in cirrhosis. Semin Liver Dis. 14:82–96. 1994. View Article : Google Scholar : PubMed/NCBI
74	Iwakiri Y: Pathophysiology of portal hypertension. Clin Liver Dis. 18:281–291. 2014. View Article : Google Scholar : PubMed/NCBI
75	Ohnishi K, Nakayama T, Saito M, Hatano H, Tsukamoto T, Terabayashi H, Sugita S, Wada K, Nomura F, Koen H, et al: Effects of propranolol on portal haemodynamics in patients with chronic liver disease. Am J Gastroenterol. 80:132–135. 1985.PubMed/NCBI
76	Mastai R, Bosch J, Navasa M, Kravetz D, Bruix J, Viola C and Rodés J: Effects of alpha-adrenergic stimulation and beta-adrenergic blockade on azygos blood flow and splanchnic haemodynamics in patients with cirrhosis. J Hepatol. 4:71–79. 1987. View Article : Google Scholar : PubMed/NCBI
77	Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T, Tsujinoue H and Fukui H: Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology. 34:745–750. 2001. View Article : Google Scholar : PubMed/NCBI
78	Schepke M, Werner E, Biecker E, Schiedermaier P, Heller J, Neef M, Stoffel-Wagner B, Hofer U, Caselmann WH and Sauerbruch T: Haemodynamic effects of the angiotensin II receptor antagonist irbesartan in patients with cirrhosis and portal hypertension. Gastroenterology. 121:389–395. 2001. View Article : Google Scholar : PubMed/NCBI