Accepted Manuscript Carvedilol versus Esophageal Variceal Band Ligation in the primary prophylaxis of variceal hemorrhage: A multicentre randomized controlled trial Hasnain Ali Shah, Zahid Azam, Javeria Rauf, Shahab Abid, Saeed Hamid, Wasim Jafri, Abdullah Khalid, Faisal Ismail, Om Parkash, Amna Subhan, Syed Mohammad Munir PII: DOI: Reference:
S0168-8278(13)00820-9 http://dx.doi.org/10.1016/j.jhep.2013.11.019 JHEPAT 4945
To appear in:
Journal of Hepatology
Received Date: Revised Date: Accepted Date:
19 July 2013 19 November 2013 20 November 2013
Please cite this article as: Ali Shah, H., Azam, Z., Rauf, J., Abid, S., Hamid, S., Jafri, W., Khalid, A., Ismail, F., Parkash, O., Subhan, A., Mohammad Munir, S., Carvedilol versus Esophageal Variceal Band Ligation in the primary prophylaxis of variceal hemorrhage: A multicentre randomized controlled trial, Journal of Hepatology (2013), doi: http://dx.doi.org/10.1016/j.jhep.2013.11.019
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Carvedilol versus Esophageal Variceal Band Ligation in the primary prophylaxis of variceal hemorrhage: A multicentre randomized controlled trial
Hasnain Ali Shah1, Zahid Azam2, Javeria Rauf1, Shahab Abid1, Saeed Hamid1, Wasim Jafri1, Abdullah Khalid2, Faisal Ismail1, Om Parkash1, Amna Subhan1, , Syed Mohammad Munir3.
1
Section of Gastroenterology, Aga Khan University, Karachi, Pakistan,
2
National
Institute of Liver & GI Diseases, Dow University of Health Sciences, Karachi, Pakistan, 3
Medical Unit VII, Jinnah Postgraduate Medical Centre, Karachi, Pakistan (ClinicalTrials.gov identifier: NCT 01070641)
Corresponding author: Prof. Hasnain Ali Shah MD (Edin.); FRCP; FACG Section of Gastroenterology, Department of Medicine, Aga Khan University, Karachi, Pakistan. Email:
[email protected] Tel no: +92-213-4864676
Fax no: +92-213-4934294
Number of figures: 3 Number of tables: 5
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List of abbreviations: EVL, Esophageal Variceal Ligation; EVB, Esophageal variceal bleed; HCV, Hepatitis C Virus;HBV, Hepatitis B virus; HDV, Hepatitis Delta virus; PVT, Portal vein Thrombosis; HCC, Hepatocellular Carcinoma; GCP, Good Clinical Practice; E.R, Emergency Room; GV, Gastric varix; EV, Esophageal varix; EKG, Electrocardiogram; BCU, Bleeding Care Unit; Hb, Hemoglobin; ITT, Intention to treat; CI, Confidence Interval; IHD, Ischemic heart disease; HVPG,
Hepatic venous pressure gradient; EGD, Esophago-gastro-
duodenoscopy; TIPS, Transjugular intrahepatic portosystemic shunt; PSE, Portosystemic encephalopathy.
CONFLICT OF INTEREST/STUDY SUPPORT: Disclosures/Conflict of Interest: • No author has to declare any conflict of interest in relation to this publication. • The statistical analysis of the entire data sets pertaining to efficacy and safety have been independently confirmed by a biostatistician who is not employed by the corporate entity • The corresponding author had full access to all of the data and takes full responsibility for the veracity of the data and analysis.
Guarantor of the article: Ethics Review Committee and Professor Hasnain Ali Shah (Corresponding author), Prof. of Medicine, Section of Gastroenterology, Aga Khan University.
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Specific author contributions: Hasnain Ali Shah and Zahid Azam contributed in terms of original idea, study design, writing protocol, organizing logistics and funding, and editing the article. Hasnain Ali Shah additionally contributed in statistical analysis and review and submission of the final manuscript. Javeria Rauf contributed in CRF, data entry and patient follow up. Shahab Abid, Wasim Jafri and Saeed Hamid contributed to study design, logistics, caring for patients under study and editing the article. Faisal Wasim, Amna Subhan and Om Parkash coordination between various departments, literature search, writing of the article with 1st author. Abdullah Khalid and Syed Muhammad Munir contributed in study design, care of study patients at their respective centers and editing of the article.
Grant Support/Acknowledgements: The research team acknowledges the unconditional support of Ferozsons Laboratories (BF Bio-Sciences), Pakistan to support this investigator initiated clinical trial in terms of bearing the cost of Carvedilol (Carvida), clinical research associate honorarium and pharmacy charges for generation of randomization sequence & dispensing of investigational products. The study was an investigator initiated clinical trial and the protocol was written by the investigators and the study was performed by the research team. The study sponsor (BF Biosciences/ Ferozsons Laboratories, Pakistan) had no role in the study design, in the collection, analysis, and interpretation of date.
3
Writing Assistance: The authors took no assistance of professional medical writers. The manuscript was written and approved by all the authors and requirements for authorship were met, and each author believes that the manuscript represents honest work.
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Introduction: Variceal bleed is a dreaded complication of portal hypertension and screening endoscopy for varices is recommended in cirrhotic patients. Varices develop at the rate of 5% per year and one third will bleed [1]. Nonselective ß-blockers (Propranolol or Nadolol) reduce portal pressure by decreasing cardiac output (ß-1 effect) and, more importantly, by producing splanchnic vasoconstriction (ß-2 effect), thereby reducing portal blood flow. A decrease in Hepatic Venous Pressure Gradient (HVPG) < 12 mmHg essentially eliminates the risk of hemorrhage and improves survival [2], while reductions
