Download PDF
Semin Liver Dis 2017; 37(01): 073-084
DOI: 10.1055/s-0036-1597891
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Design of Clinical Trials in Portal Hypertension

Juan G. Abraldes
1   Cirrhosis Care Clinic, Division of Gastroenterology (Liver Unit), University of Alberta, CEGIIR, Edmonton, Canada
,
Guadalupe Garcia-Tsao
2   Digestive Diseases Section, Yale University School of Medicine, New Haven, Connecticut
3   Digestive Diseases Section, VA-CT Healthcare System, West Haven, Connecticut
› Author Affiliations
Further Information

Publication History

Publication Date:
15 February 2017 (online)

    Permissions and Reprints

Abstract

Portal hypertension (PH) is the main consequence of cirrhosis and is responsible for the majority of its complications. Gastroesophageal varices and variceal hemorrhage are direct consequences of PH; therefore, most clinical trials in PH have been directed toward treating or preventing variceal hemorrhage. However, varices and variceal hemorrhage are not isolated events; they must be considered in the context of the presence (or absence) of other complications of cirrhosis/PH. Cirrhosis progresses across different stages, each with a different prognosis and pathophysiology and hence different therapeutic targets. In this review, the authors discuss the design of proof-of-concept studies for the assessment of new drugs for the treatment of PH, that are mainly based on the drug's ability to reduce the hepatic venous pressure gradient. They further discuss the design of studies with clinical endpoints in the context of each stage of cirrhosis, specifically targets of therapy, optimal therapies in the control arm, risk stratification, and primary outcome.

Keywords

cirrhosis - portal hypertension - clinical trials - hepatic venous pressure gradient
 

  • References

  • 1 GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015; 385 (9963): 117-171
    CrossrefPubMedGoogle Scholar
  • 2 D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006; 44 (1) 217-231
    CrossrefPubMedGoogle Scholar
  • 3 de Francis R. Expanding consensus in portal hypertension. Report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol 2015; 63 (3) 743-752
    CrossrefPubMedGoogle Scholar
  • 4 Ripoll C, Bari K, Garcia-Tsao G. Serum albumin can identify patients with compensated cirrhosis with a good prognosis. J Clin Gastroenterol 2015; 49 (7) 613-619
    CrossrefPubMedGoogle Scholar
  • 5 Bruno S, Saibeni S, Bagnardi V , et al; AISF (Italian Association for the Study of the Liver) – EPA-SCO Collaborative Study Group. Mortality risk according to different clinical characteristics of first episode of liver decompensation in cirrhotic patients: a nationwide, prospective, 3-year follow-up study in Italy. Am J Gastroenterol 2013; 108 (7) 1112-1122
    CrossrefPubMedGoogle Scholar
  • 6 Lagakos SW. The challenge of subgroup analyses--reporting without distorting. N Engl J Med 2006; 354 (16) 1667-1669
    CrossrefPubMedGoogle Scholar
  • 7 Groszmann RJ, Garcia-Tsao G, Bosch J , et al; Portal Hypertension Collaborative Group. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med 2005; 353 (21) 2254-2261
    CrossrefPubMedGoogle Scholar
  • 8 Ripoll C, Groszmann R, Garcia-Tsao G , et al; Portal Hypertension Collaborative Group. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology 2007; 133 (2) 481-488
    CrossrefPubMedGoogle Scholar
  • 9 Ripoll C, Groszmann R, Garcia-Tsao G , et al. Hepatic venous pressure gradient (HVPG) predicts the development of hepatocellular carcinoma (HCC) independently of severity of cirrhosis. J Hepatol 2009; 50 (5) 923-928
    CrossrefPubMedGoogle Scholar
  • 10 Bruix J, Castells A, Bosch J , et al. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology 1996; 111 (4) 1018-1022
    CrossrefPubMedGoogle Scholar
  • 11 Lebrec D, De Fleury P, Rueff B, Nahum H, Benhamou JP. Portal hypertension, size of esophageal varices, and risk of gastrointestinal bleeding in alcoholic cirrhosis. Gastroenterology 1980; 79 (6) 1139-1144
    PubMedGoogle Scholar
  • 12 Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO, Atterbury CE, Glickman M. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology 1985; 5 (3) 419-424
    CrossrefPubMedGoogle Scholar
  • 13 Bruno S, Zuin M, Crosignani A , et al. Predicting mortality risk in patients with compensated HCV-induced cirrhosis: a long-term prospective study. Am J Gastroenterol 2009; 104 (5) 1147-1158
    CrossrefPubMedGoogle Scholar
  • 14 D'Amico G, Pasta L, Morabito A , et al. Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients. Aliment Pharmacol Ther 2014; 39 (10) 1180-1193
    CrossrefPubMedGoogle Scholar
  • 15 Villanueva C, Albillos A, Genescà J , et al. Development of hyperdynamic circulation and response to β-blockers in compensated cirrhosis with portal hypertension. Hepatology 2016; 63 (1) 197-206
    CrossrefPubMedGoogle Scholar
  • 16 Salerno F, Borroni G, Moser P , et al. Survival and prognostic factors of cirrhotic patients with ascites: a study of 134 outpatients. Am J Gastroenterol 1993; 88 (4) 514-519
    PubMedGoogle Scholar
  • 17 Bernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V. Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis. J Hepatol 2015; 63 (5) 1272-1284
    CrossrefPubMedGoogle Scholar
  • 18 Moreau R, Jalan R, Gines P , et al; CANONIC Study Investigators of the EASL–CLIF Consortium. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013; 144 (7) 1426-1437 , 1437.e1–1437.e9
    CrossrefPubMedGoogle Scholar
  • 19 Bajaj JS, O'Leary JG, Reddy KR , et al; North American Consortium For The Study Of End-Stage Liver Disease Nacseld; North American Consortium For The Study Of End-Stage Liver Disease (NACSELD). Survival in infection-related acute-on-chronic liver failure is defined by extrahepatic organ failures. Hepatology 2014; 60 (1) 250-256
    CrossrefPubMedGoogle Scholar
  • 20 Groszmann RJ, Wongcharatrawee S. The hepatic venous pressure gradient: anything worth doing should be done right. Hepatology 2004; 39 (2) 280-282
    CrossrefPubMedGoogle Scholar
  • 21 Perelló A, Escorsell A, Bru C , et al. Wedged hepatic venous pressure adequately reflects portal pressure in hepatitis C virus-related cirrhosis. Hepatology 1999; 30 (6) 1393-1397
    CrossrefPubMedGoogle Scholar
  • 22 Abraldes JG, Tarantino I, Turnes J, Garcia-Pagan JC, Rodés J, Bosch J. Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis. Hepatology 2003; 37 (4) 902-908
    CrossrefPubMedGoogle Scholar
  • 23 D'Amico G, Garcia-Pagan JC, Luca A, Bosch J. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology 2006; 131 (5) 1611-1624
    CrossrefPubMedGoogle Scholar
  • 24 Villanueva C, Aracil C, Colomo A , et al. Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding. Gastroenterology 2009; 137 (1) 119-128
    CrossrefPubMedGoogle Scholar
  • 25 La Mura V, Abraldes JG, Raffa S , et al. Prognostic value of acute hemodynamic response to i.v. propranolol in patients with cirrhosis and portal hypertension. J Hepatol 2009; 51 (2) 279-287
    CrossrefPubMedGoogle Scholar
  • 26 Zafra C, Abraldes JG, Turnes J , et al. Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis. Gastroenterology 2004; 126 (3) 749-755
    CrossrefPubMedGoogle Scholar
  • 27 Garcia-Tsao G, Grace ND, Groszmann RJ , et al. Short-term effects of propranolol on portal venous pressure. Hepatology 1986; 6 (1) 101-106
    CrossrefPubMedGoogle Scholar
  • 28 Bañares R, Moitinho E, Piqueras B , et al. Carvedilol, a new nonselective beta-blocker with intrinsic anti- Alpha1-adrenergic activity, has a greater portal hypotensive effect than propranolol in patients with cirrhosis. Hepatology 1999; 30 (1) 79-83
    CrossrefPubMedGoogle Scholar
  • 29 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 (5) 1401-1407
    CrossrefPubMedGoogle Scholar
  • 30 Bañares R, Moitinho E, Matilla A , et al. Randomized comparison of long-term carvedilol and propranolol administration in the treatment of portal hypertension in cirrhosis. Hepatology 2002; 36 (6) 1367-1373
    CrossrefPubMedGoogle Scholar
  • 31 Chalasani N. Getting new drugs approved in portal hypertension: problems and proposals. Curr Hepatology Rep 2016; 15 (3) 187-189
    CrossrefPubMedGoogle Scholar
  • 32 Blasco A, Forns X, Carrión JA , et al. Hepatic venous pressure gradient identifies patients at risk of severe hepatitis C recurrence after liver transplantation. Hepatology 2006; 43 (3) 492-499
    CrossrefPubMedGoogle Scholar
  • 33 Nagula S, Jain D, Groszmann RJ, Garcia-Tsao G. Histological-hemodynamic correlation in cirrhosis-a histological classification of the severity of cirrhosis. J Hepatol 2006; 44 (1) 111-117
    CrossrefPubMedGoogle Scholar
  • 34 Garcia-Tsao G, Friedman S, Iredale J, Pinzani M. Now there are many (stages) where before there was one: In search of a pathophysiological classification of cirrhosis. Hepatology 2010; 51 (4) 1445-1449
    CrossrefPubMedGoogle Scholar
  • 35 Marcellin P, Gane E, Buti M , et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 2013; 381 (9865): 468-475
    CrossrefPubMedGoogle Scholar
  • 36 Bosch J, Groszmann RJ, Shah VH. Evolution in the understanding of the pathophysiological basis of portal hypertension: How changes in paradigm are leading to successful new treatments. J Hepatol 2015; 62 (1, Suppl): S121-S130
    CrossrefPubMedGoogle Scholar
  • 37 Yoon YJ, Friedman SL, Lee YA. Antifibrotic therapies: where are we now?. Semin Liver Dis 2016; 36 (1) 87-98
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Abraldes JG, Albillos A, Bañares R , et al. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology 2009; 136 (5) 1651-1658
    CrossrefPubMedGoogle Scholar
  • 39 Mohanty A, Tate JP, Garcia-Tsao G. Statins are associated with a decreased risk of decompensation and death in veterans with hepatitis C-related compensated cirrhosis. Gastroenterology 2016; 150 (2) 430-40.e1
    CrossrefPubMedGoogle Scholar
  • 40 Lens S, Rincón D, García-Retortillo M , et al. Association between severe portal hypertension and risk of liver decompensation in patients with hepatitis C, regardless of response to antiviral therapy. Clin Gastroenterol Hepatol 2015; 13 (10) 1846-1853.e1
    CrossrefPubMedGoogle Scholar
  • 41 Sack J, Garcia-Tsao G. Variceal hemorrhage in a patient with hepatitis C virus cirrhosis in whom liver synthetic function had normalized after viral elimination. Hepatology 2016; 63 (5) 1733-1735
    CrossrefPubMedGoogle Scholar
  • 42 Hernández-Gea V, Aracil C, Colomo A , et al. Development of ascites in compensated cirrhosis with severe portal hypertension treated with β-blockers. Am J Gastroenterol 2012; 107 (3) 418-427
    CrossrefPubMedGoogle Scholar
  • 43 D'Amico G, De Franchis R ; Cooperative Study Group. Upper digestive bleeding in cirrhosis. Post-therapeutic outcome and prognostic indicators. Hepatology 2003; 38 (3) 599-612
    PubMedGoogle Scholar
  • 44 Reverter E, Tandon P, Augustin S , et al. A MELD-based model to determine risk of mortality among patients with acute variceal bleeding. Gastroenterology 2014; 146 (2) 412-19.e3
    CrossrefPubMedGoogle Scholar
  • 45 Fortune B, Garcia-Tsao G, Ciarleglio M , et al. Child-Turcotte-Pugh Class Is Best at Stratifying Risk in Variceal Hemorrhage: Analysis of a U.S. Multi-Center Prospective Study. J Clin Gastroenterol 2016; DOI: 10.1097/MCG.0000000000000733.
    PubMedGoogle Scholar
  • 46 Moitinho E, Escorsell A, Bandi JC , et al. Prognostic value of early measurements of portal pressure in acute variceal bleeding. Gastroenterology 1999; 117 (3) 626-631
    CrossrefPubMedGoogle Scholar
  • 47 Villanueva C, Ortiz J, Miñana J , et al. Somatostatin treatment and risk stratification by continuous portal pressure monitoring during acute variceal bleeding. Gastroenterology 2001; 121 (1) 110-117
    CrossrefPubMedGoogle Scholar
  • 48 Abraldes JG, Tandon P. Soft and hard endpoints in acute variceal bleeding. Hepatology 2015; 61 (3) 762-765
    CrossrefPubMedGoogle Scholar
  • 49 García-Pagán JC, Caca K, Bureau C , et al; Early TIPS (Transjugular Intrahepatic Portosystemic Shunt) Cooperative Study Group. Early use of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med 2010; 362 (25) 2370-2379
    CrossrefPubMedGoogle Scholar
  • 50 Abraldes JG, Villanueva C, Bañares R , et al; Spanish Cooperative Group for Portal Hypertension and Variceal Bleeding. Hepatic venous pressure gradient and prognosis in patients with acute variceal bleeding treated with pharmacologic and endoscopic therapy. J Hepatol 2008; 48 (2) 229-236
    CrossrefPubMedGoogle Scholar
  • 51 Amitrano L, Guardascione MA, Manguso F , et al. The effectiveness of current acute variceal bleed treatments in unselected cirrhotic patients: refining short-term prognosis and risk factors. Am J Gastroenterol 2012; 107 (12) 1872-1878
    CrossrefPubMedGoogle Scholar
  • 52 Garcia-Tsao G. The Child-Turcotte classification: From Gestalt to sophisticated statistics and back. Dig Dis Sci 2016; 61 (11) 3102-3104
    CrossrefPubMedGoogle Scholar
  • 53 Bosch J, Thabut D, Albillos A , et al; International Study Group on rFVIIa in UGI Hemorrhage. Recombinant factor VIIa for variceal bleeding in patients with advanced cirrhosis: a randomized, controlled trial. Hepatology 2008; 47 (5) 1604-1614
    CrossrefPubMedGoogle Scholar
  • 54 Tandon P, Abraldes JG, Keough A , et al. Risk of bacterial infection in patients with cirrhosis and acute variceal hemorrhage, based on Child-Pugh class, and effects of antibiotics. Clin Gastroenterol Hepatol 2015; 13 (6) 1189-96.e2
    CrossrefPubMedGoogle Scholar
  • 55 Augustin S, Muntaner L, Altamirano JT , et al. Predicting early mortality after acute variceal hemorrhage based on classification and regression tree analysis. Clin Gastroenterol Hepatol 2009; 7 (12) 1347-1354
    CrossrefPubMedGoogle Scholar
  • 56 Seo YS, Park SY, Kim MY , et al. Lack of difference among terlipressin, somatostatin, and octreotide in the control of acute gastroesophageal variceal hemorrhage. Hepatology 2014; 60 (3) 954-963
    CrossrefPubMedGoogle Scholar
  • 57 Calès P, Lacave N, Silvain C, Vinel JP, Besseghir K, Lebrec D. Prospective study on the application of the Baveno II consensus conference criteria in patients with cirrhosis and gastrointestinal bleeding. J Hepatol 2000; 33 (5) 738-741
    CrossrefPubMedGoogle Scholar
  • 58 Thabut D, Rudler M, Dib N , et al; French Club for the Study of Portal Hypertension (CFEHTP). Multicenter prospective validation of the Baveno IV and Baveno II/III criteria in cirrhosis patients with variceal bleeding. Hepatology 2015; 61 (3) 1024-1032
    CrossrefPubMedGoogle Scholar
  • 59 de Franchis R. Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2005; 43 (1) 167-176
    CrossrefPubMedGoogle Scholar
  • 60 de Franchis R ; Baveno V Faculty. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2010; 53 (4) 762-768
    CrossrefPubMedGoogle Scholar
  • 61 Planas R, Ballesté B, Alvarez MA , et al. Natural history of decompensated hepatitis C virus-related cirrhosis. A study of 200 patients. J Hepatol 2004; 40 (5) 823-830
    CrossrefPubMedGoogle Scholar
  • 62 Feu F, García-Pagán JC, Bosch J , et al. Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis. Lancet 1995; 346 (8982): 1056-1059
    CrossrefPubMedGoogle Scholar
  • 63 Villanueva C, López-Balaguer JM, Aracil C , et al. Maintenance of hemodynamic response to treatment for portal hypertension and influence on complications of cirrhosis. J Hepatol 2004; 40 (5) 757-765
    CrossrefPubMedGoogle Scholar
  • 64 Augustin S, González A, Badia L , et al. Long-term follow-up of hemodynamic responders to pharmacological therapy after variceal bleeding. Hepatology 2012; 56 (2) 706-714
    CrossrefPubMedGoogle Scholar
  • 65 Sauerbruch T, Mengel M, Dollinger M , et al; German Study Group for Prophylaxis of Variceal Rebleeding. Prevention of Rebleeding From Esophageal Varices in Patients With Cirrhosis Receiving Small-Diameter Stents Versus Hemodynamically Controlled Medical Therapy. Gastroenterology 2015; 149 (3) 660-8.e1
    CrossrefPubMedGoogle Scholar
  • 66 Zipprich A, Garcia-Tsao G, Rogowski S, Fleig WE, Seufferlein T, Dollinger MM. Prognostic indicators of survival in patients with compensated and decompensated cirrhosis. Liver Int 2012; 32 (9) 1407-1414
    CrossrefPubMedGoogle Scholar
  • 67 Kanwal F, Hays RD, Kilbourne AM, Dulai GS, Gralnek IM. Are physician-derived disease severity indices associated with health-related quality of life in patients with end-stage liver disease?. Am J Gastroenterol 2004; 99 (9) 1726-1732
    CrossrefPubMedGoogle Scholar
  • 68 García-Pagán JC, Villanueva C, Albillos A , et al; Spanish Variceal Bleeding Study Group. Nadolol plus isosorbide mononitrate alone or associated with band ligation in the prevention of recurrent bleeding: a multicentre randomised controlled trial. Gut 2009; 58 (8) 1144-1150
    CrossrefPubMedGoogle Scholar
  • 69 Kumar A, Jha SK, Sharma P , et al. Addition of propranolol and isosorbide mononitrate to endoscopic variceal ligation does not reduce variceal rebleeding incidence. Gastroenterology 2009; 137 (3) 892-901 , 901.e1
    CrossrefPubMedGoogle Scholar
  • 70 Abraldes JG, Villanueva C, Aracil C , et al; BLEPS Study Group. Addition of simvastatin to standard therapy for the prevention of variceal rebleeding does not reduce rebleeding but increases survival in patients with cirrhosis. Gastroenterology 2016; 150 (5) 1160-1170.e3
    CrossrefPubMedGoogle Scholar
  • 71 de la Peña J, Brullet E, Sanchez-Hernández E , et al. Variceal ligation plus nadolol compared with ligation for prophylaxis of variceal rebleeding: a multicenter trial. Hepatology 2005; 41 (3) 572-578
    CrossrefPubMedGoogle Scholar
  • 72 Thiele M, Albillos A, Abazi R, Wiest R, Gluud LL, Krag A. Non-selective beta-blockers may reduce risk of hepatocellular carcinoma: a meta-analysis of randomized trials. Liver Int 2015; 35 (8) 2009-2016
    CrossrefPubMedGoogle Scholar