This study is a real-time evaluation of a large data set of patients who received either terlipressin or octreotide as an adjunct to endoscopic intervention in patients with EVB
The rationale for the use of vasoactive drugs was to produce splanchnic vasoconstriction and reduce inflow of portal blood and portal pressure. (9) Overall, a higher proportion of patients in our center received terlipressin relative to octreotide, since terlipressin has been shown to effectively control EVB, decrease the requirement of blood transfusion and increase survival. (4) There have been several trials that analyzed terlipressin and octreotide on a head-to-head efficacy basis. Early data suggested a greater effect of terlipressin over octreotide at reducing variceal pressure, and that prompted researchers to recommend terlipressin as the first choice, followed by octreotide or somatostatin as the second choice agents. (10, 11) However, many other studies that compared the different vasoactive drugs as monotherapy found no significant difference in the treatment response in patients with esophageal variceal bleeding. (12)
Studies have acknowledged the importance of Child-Pugh classification as being an independent mortality-predicting factor in EVB but no differences in mortality were noted between the two treatment groups when the analysis was performed based on the Child-Pugh classification. (13) Majority of our study subjects were males. Most of the patients had advanced liver disease with Child-Pugh Class C. It is known that terlipressin which is a potent vasoconstrictor, can provoke severe dysrhythmias and ischemic complications, and hence it should be used with caution in patients with preexisting ischemic heart or cerebral disease. (14)
We found that there was no significant difference in achieving control of bleeding after endoscopy for the two treatment groups. Several meta-analyses support this notion and neither of the two drugs is preferred over the other in achieving early control of bleeding. Zou et al in their network meta-analysis conducted in 2019, consisting of 2187 patients found no statistically significant difference with respect to initial control of bleeding. (15) Another meta-analysis conducted in 2012 with data from 1978 to 2008 consisting of 3111 patients with 30 trials failed to prefer any one of the vasoactive drugs over the other over the efficacy of control of bleeding (16). Similar findings were also reported by Seo et al. in their randomized control trial conducted in 2014. (12) Our present series of large data sets also observed that there were no significant differences in terlipressin and octreotide when used as adjuvant therapy in the management of control of variceal bleeding. This study is also in line with similar findings in our previous randomized controlled trial where we randomly gave terlipressin or octreotide to 164 patients in each arm.
In the present series of patients with variceal bleeding, we found that octreotide was associated with a slightly increased length of hospital stay when compared to terlipressin (OR: 1.59) Our previous study conducted in 2009 also had similar findings. (17). On the contrary, Corley et al. reported a 47% lower risk of complications with Octreotide than with Terlipressin, and a 69% lower risk of presenting major complications, hence shorter hospital stays. (18)
Individual factors that could likely prolong hospital stay were analyzed in our study. In a Cox regression analysis, factors including high pulse raised bilirubin levels, cardiac events during hospital stay, and presence of portosystemic encephalopathy (PSE) at presentation were all predictors of increased length of hospital stay. Increased pulse in the emergency was associated with an increase in hospital stay. Increased total bilirubin and PSE at presentation were found to be linked with an increased hospital stay. These are well-documented and known facts as both signify the extent of disease progression that can later influence the longevity of its management. Jha et al. state in their terlipressin-focused study that median total bilirubin played a role in the failure of treatment via terlipressin and also influenced early rebleeding. (19) D’Amico et al. also stated that bilirubin levels and the presence of encephalopathy are considered to be independent factors predictive of re-bleeding and mortality, which further supports our study findings. (20)
Control of variceal bleeding after EGD was associated with a decreased length of hospital stay. A review article in 2015 analyzed five comprehensive studies of randomized control trials that accounted for rebleeding in patients treated with vasopressin/terlipressin or somatostatin/octreotide and found no difference in the rebleeding rate between patients treated with either. (2) Therefore our study findings could be attributable to the fact there were more patients with higher MELD scores in our octreotide group and hence more sick patients and relatively longer hospital stay. Moreover, the differences in the hospital stay are practically less than a day which in our opinion is not clinically important.
Six-week mortality was assessed in which cardiac events during hospital stay, PSE, control of variceal bleeding after EGD, total bilirubin, and serum albumin were found to be independent factors influencing/ predicting mortality. Low albumin can increase the chances of mortality. Hence it is combined with terlipressin or octreotide while treating EVB. (21, 22)
Our study suggests no significant difference in mortality between groups that received terlipressin or octreotide. This is consistent with recent trials comparing the two drugs. (12)
A Cochrane systematic review conducted in 2003 recommended the use of Terlipressin as the vasoactive drug of choice in acute variceal bleeding, as it had a 34% relative risk reduction in mortality. (23) A recent meta-analysis showed that there was no significant difference in mortality with the use of different vasoactive drugs, but terlipressin was observed to have a better response to other outcomes such as rebleeding and requirement for blood transfusion. (24) Another meta-analysis consisting of over 2000 patients concluded that octreotide was the safest vasoactive drug, with the lowest risk of adverse events (9.1%) and serious adverse events (0.0%) compared to other drugs. (15)
Achieving early control of variceal bleeding leads to decreased mortality (OR: 0.09). Although EVB-related mortality at 6 weeks has decreased to approximately 10–20% in the last decades, it is still significant. (25, 26) Patients presenting with rebleeding were found to have higher cases of mortality. (2) The rebleeding risk in patients who survive an episode of EVB is very high; 63% at 1 to 2 years with a mortality of 33%. (27)
While comparing the outcomes of the two drugs for EVB, it was observed that the differences between cardiac events during hospital stay, achieving control of variceal bleeding, number of packed cell transfusions received, length of hospital stay, and six-weeks mortality were found to be not statistically significant. When looking for cardiac events we accounted for acute coronary syndrome and arrhythmias requiring intervention. Azam et al. found relevant differences in their study with cardiac effects in comparison to terlipressin and octreotide. They shared an isolated event of a patient with no previous cardiac history who was initiated on terlipressin but developed ECG changes and was shifted to octreotide. (28)
Cardiac events during hospital stay proved to be a major mortality-predicting factor having an adjusted OR of 11.22(3.60–35.0). Having pre-existing cardiac conditions puts one at risk of developing further cardiac conditions during stressful body states such as EVB. Although our study did not specify differences in our drug groups playing a role in predicting mortality, a recent meta-analysis consisting of 21 RCTs with a total of 2,431 patients identified the risk to be similar between the two drug groups. (13)
Overall, our study did not find much difference in the use of terlipressin and octreotide in terms of mortality. There is some statistically significant difference in terms of prolonged hospital stay but, in our opinion, this has no clinical significance. Moreover, several other facts have been reinforced in our study which include factors such as low hemoglobin, high Child score, high bilirubin levels, and low albumin lead to higher morbidity and mortality in patients who develop esophageal variceal bleeding.
Some of the limitations in our study include a relatively larger number of patients in the terlipressin group compared to octreotide, which may influence the comparison. This also reflects a potential selection bias as the allocation of medicine was at the physician’s discretion. The retrospective nature of this study cannot take care of some other unknown confounders. Moreover, hemodynamic studies/ hepatic flow studies (Hepatic Venous Pressure Gradient and Portal venous flow) were not done which could have contributed to providing factors of importance while comparing the control of bleeding and survival outcome between groups.
Our study's strength lies in the fact that the results of the present series are based upon the analysis of a large data set, hence the comparison between a large number of patients is meaningful. This study also does not have any observer bias as physicians and patients were not aware of any ongoing study, hence ruling out the possibility of influencing and modulating their treatment behavior, decision-making, and documentation.
In conclusion, both agents have similar outcomes in terms of control of bleeding, hospital stay, mortality, and side effects. There is no difference in the cardiac effects outcome in the groups. Both agents are safe to use in variceal bleeding management.