Abstract
Background
Current guidelines lack clarity about the optimal duration of octreotide therapy for patients with esophageal variceal hemorrhage (EVH). To address this lack of evidence, we conducted a randomized clinical trial (RCT) of 24-hours versus 72-hours continuous infusion of octreotide for patients with EVH.
Methods
This multi-center, prospective RCT (NCT03624517), randomized patients with EVH to 24-hour versus 72-hour infusion of octreotide. Patients were required to undergo esophageal variceal band ligation prior to enrollment. The primary endpoint was rebleeding rate at 72 hours. The study was terminated early due to an inability to recruit during and after the COVID-19 epidemic.
Results
For patients randomized to 72-hours (n = 19) of octreotide vs 24-hours (n = 15), there were no differences in the need for transfusion, average pRBC units transfused per patient (3 units vs 2 units), infection (5% vs 0%), mechanical ventilation (11% vs 7%), or the need for vasopressors (5% vs 3%), respectively (none of these differences were statistically significantly different). There were 2 re-bleeding events in the 72-hour group (11%), and no re-bleeding events in the 24-hour group (p = 0.49). 8/15 of patients receiving 24 hours of octreotide were discharged at or before hospital day 3 while none in the 72-hour group was discharged before day 3 (p < 0.001). There was one death (in the 72-hour group) within 30 days.
Conclusions
A 24-hour infusion is non-inferior to a 72-hour infusion of octreotide for prevention of re-bleeding in patients with EVH. We propose that shortened octreotide duration may help reduce hospital stay and related costs in these patients.
Keywords: hemorrhage, cirrhosis, portal hypertension, gastrointestinal bleeding, somatostatin
Introduction
Esophageal variceal hemorrhage due to portal hypertension is a devastating clinical complication in patients with cirrhosis which is associated with significant morbidity and mortality.1 It is typically managed with pharmacologic, endoscopic, and radiological techniques. The current standard of care includes intravenous infusion of the somatostatin analogue, octreotide, started as soon as variceal hemorrhage is suspected, followed by urgent or emergent endoscopy, and treatment typically with esophageal variceal band ligation (EBL) within 8 to 24 hours.2–4 Current guidelines recommend the continuation of octreotide for 2 to 5 days after confirmation of variceal bleeding and subsequent EBL.5,6
The rationale for using octreotide is that it reduces portal blood flow, which reduces portal pressure, and thus, the propensity for variceal bleeding.1 The pharmacology of octreotide suggests that the benefits are transient due to rapid desensitization and tachyphylaxis.7 Additionally, the appropriate duration of continuous octreotide infusion is largely based on expert opinion.5 Here, we hypothesized that because of the development of rapid tachyphylaxis, prolonged infusion is likely to be unnecessary after EBL, and may inappropriately increase hospital and medical costs. Therefore, we performed a randomized clinical trial (RCT) to help better define the optimal duration of octreotide therapy for patients with esophageal variceal hemorrhage.
Methods
Study setting and design
This was a prospective, multi-center, randomized controlled trial that compared the efficacy of 24-hours versus 72-hour octreotide infusion in preventing early rebleeding after successful EBL in patients with EVH (NCT03624517). The study was conducted across 6 sites in the United States (Appendix 1). The trial was begun on May 21, 2018 and closed on May 22, 2024. Recruitment was halted during the COVID-19 epidemic, and because study sites were unable to meet recruitment goals after the epidemic, the Data Safety and Monitoring board recommended closure of the study.
Inclusion and exclusion criteria
Adult patients (age ≥18 years) presenting with suspected upper gastrointestinal bleeding (GIB) due to esophageal varices were potentially eligible for inclusion. Inclusion criteria included patients with evidence or suspicion of upper gastrointestinal bleeding (GIB) at presentation, defined by symptoms of melena, hematemesis, or bright red blood per rectal exam, accompanied by hypotension (systolic blood pressure <90mmHg and diastolic blood pressure <60mmHg) and tachycardia (hear rate >155 beats per minute). Patients were required to have known or suspected cirrhosis – either by histological evidence or based on specific clinical and imaging criteria, including: 1) a nodular appearing liver on ultrasound or cross-sectional imaging (computed tomography (CT), or magnetic resonance imaging (MRI)), 2) splenomegaly, 3) varices documented on cross sectional imaging. Further, eligible patients had to have bleeding esophageal varices requiring EBL, and they or a legally authorized representative had to be able to provide informed consent. As per current standard of care management for patients with upper GIB and known or suspected cirrhosis, all patients were begun on empiric intravenous octreotide at the time of admission, and were being treated with an octreotide infusion the time of the endoscopy. Exclusion criteria included known upper gastrointestinal malignancy, bleeding from gastric varices, use of endoscopic methods other than EBL to control bleeding, variceal bleeding within the last 90 days, history of transjugular intrahepatic portosystemic shunt (TIPS), pregnancy, incarcerated individuals, recent severe illness (myocardial infarction, cerebrovascular accident, sepsis, respiratory failure) within the previous 6 weeks, known or suspected allergy to octreotide, or no need for EBL. Patients in whom EBL was unsuccessful in controlling bleeding were also planned to be excluded.
Randomization and intervention
Randomization by computer-generated blocked randomization was conducted for all enrolled subjects by the central study coordinator at the Medical University of South Carolina (MUSC). The randomization schedule was blinded in sequentially numbered opaque envelopes. Patients were randomized to receive octreotide as a continuous intravenous infusion for 24-hours or 72-hours after it was started. Following standard-of-care for variceal bleeding, all patients were monitored in the hospital for at least 72 hours after undergoing esophagogastroduodenoscopy (EGD) and EBL. Any recurrent bleeding was managed per standard-of-care which may have included a combination of octreotide infusion, placement of an esophageal balloon tamponade tube (i.e. Minnesota tube, or similar), repeat endoscopic intervention, or transjugular intrahepatic portocaval shunt (TIPS) placement.
Outcome measures
The primary outcome of this study was the incidence of re-bleeding within 72-hours after achieving hemostasis with EBL. Rebleeding was defined as any of the following: a drop in hemoglobin (Hb) by > 20% from baseline, sustained tachycardia above 100 beats/min, transfusion of > 2 units of packed red blood cells, recurrence of hematemesis or ongoing melena. Secondary outcomes included transfusion requirements, dysphagia/odynophagia, TIPS placement, hospital length of stay (LOS), and death within 30 days. Other measures recorded were use of vasopressors, mechanical ventilation for > 12 hours, nasogastric tube insertion.
Statistical analysis
The study was originally designed as a non-inferiority study. Primary hemostasis of esophageal bleeding is highly successful (90%), despite rebleeding rates of 10–30%.8,9 Assuming a primary hemostasis rate of 90% and a non-inferiority margin of 15%, 69 patients were estimated to be needed in each group to achieve 90% power. This calculation assumed a type I error rate of 0.05 and equal sample sizes. Anticipating patient drop-out of approximately 15%, a sample size of 80 patients in each group was intended.
Given the small number of participants, we did not examine statistical differences in baseline clinical demographics, clinical presentation, or laboratory tests. Comparisons of outcomes were however examined (using the Mann-Whitney test or the Fisher’s Exact test). A value was considered statistically significant at a two tailed test of P≤0.05. Statistical analysis was performed using SPSS V28 (2021; IBM Corp., Armonk, New York, USA).
Results
Participants
We screened 69 potential participants, of whom 33 failed to meet the eligibility criteria and 2 refused to participate (Figure 1). Thirty-four participants were eligible, of whom 15 were assigned to the 24-hour arm and 19 to the 72-hour arm. Overall, 38% of participants were female, 79% were white, and 85% were of non-Hispanic ethnicity (Table 1). The mean ages were similar in both groups - 54 ± 11 years for the 72-hour group and 52 ± 16 years for the 24-hour group. Both groups had more males. The predominant etiology of cirrhosis was alcohol in both groups, followed by metabolic-dysfunction associated steatohepatitis (MASH) (21%) in the 72-hour group and hepatitis C virus (HCV) (27%) in the 24-hour group. The Rockall score was calculated for each cohort, and both had an average of 3 (SD 1), which corresponded to a re-bleeding risk of 11.2%.10 The prevalence of comorbidities varied, with gastroesophageal reflux disease (GERD) (32% vs 7%), hypertension (32% vs 20%), and diabetes mellitus (37% vs 20%), higher in the 72-hour group.
Figure 1.
Patients. A consort diagram illustrating participant recruitment into the trial is shown.
Table 1.
Baseline characteristics
| 72-hr octreotide N=19 | 24-hr octreotide N=15 | |
|---|---|---|
| Demographics | ||
| Age (mean ± SD) | 54 ± 11 | 52 ± 16 |
| Sex | ||
| Female, n (%) | 6 (32 %) | 7 (47 %) |
| Race | ||
| White, n (%) | 16 (84 %) | 11 (73 %) |
| Black, n (%) | 0 (0 %) | 3 (20 %) |
| Other, n (%) | 3 (16 %) | 1 (7 %) |
| Ethnicity | ||
| Non-Hispanic/Latino, n (%) | 16 (84 %) | 13 (87 %) |
| Hispanic/Latino, n (%) | 3 (16 %) | 2 (13 %) |
| Cirrhosis etiology | ||
| Alcohol | 14 (74 %) | 7 (47 %) |
| HCV | 1 (5 %) | 4 (27 %) |
| MASH | 4 (21 %) | 1 (7 %) |
| Unknown | 0 (0 %) | 3 (20 %) |
| History of decompensating event | ||
| Ascites | 9 (47 %) | 8 (5 %) |
| Hepatic encephalopathy | 4 (21 %) | 4 (3 %) |
| Hepatorenal syndrome | 1 (5 %) | 0 (0 %) |
| Comorbidities | ||
| GERD | 6 (32 %) | 1 (7 %) |
| Peptic ulcer disease | 1 (5 %) | 1 (7 %) |
| Hypertension | 6 (32 %) | 3 (20 %) |
| Diabetes mellitus | 7 (37 %) | 3 (20 %) |
| Coronary artery disease | 1 (5 %) | 0 (0 %) |
| Asthma | 2 (11 %) | 0 (0 %) |
| Chronic kidney disease | 0 (0 %) | 2 (13 %) |
| Obesity (BMI> 30) | 4 (21 %) | 2 (13 %) |
| Malignancy | 2 (11 %) | 2 (13 %) |
| Rockall score (pre-endoscopy; mean ± SD) | 3 ± 1 | 3 ± 1 |
Abbreviations: GERD - gastroesophageal reflux disease; BMI - body mass index
The initial clinical presentation for both groups was largely hematemesis (84% and 67% in the 72-hour and 24-hour group, respectively). Vital signs and baseline laboratory values were comparable between both groups. Both cohorts had similar levels of hemoglobin (8.4 ± 2.6 vs. 8.3 ± 1.4 g/dL), hematocrit (27 ± 6 vs. 25 ± 7%), sodium (135 ± 3 vs. 136 ± 5 mmol/L), total bilirubin (5.0 ± 12.8 vs. 4.3 ± 5.9 mg/dL), creatinine (1.0 ± 0.4 vs. 1.3 ± 1.3 mg/dL),and INR (1.6 ± 0.5 vs. 1.7 ± 0.7). Albumin levels were higher in the 72-hour octreotide group (2.7 ± 0.5 vs. 3.1 ± 0.6 g/dL, p = 0.02). The 72-hour octreotide cohort had a higher prevalence of ascites (47% vs 5%), hepatic encephalopathy (21% vs 3%), and hepatorenal syndrome (5% vs 0%).
The need for mechanical ventilation (11% vs 7%) and vasopressors (5% vs 3%) were similar in the 2 groups. NG tube placement was performed in 2 of patients (11%) in the 72-hour octreotide group, and in none for the 24-hour octreotide group.
Primary outcome
Overall, 2 patients had re-bleeding; one patient in the 72-hour octreotide group had a re-bleeding event (5%) within 72 hours and another patient in this group rebled after 4 days (5%). There were no rebleeding events in the 24-hour octreotide group.
Secondary outcomes
The need for transfusions was higher in the 24-hour group (80%) compared to the 72-hour group (53%), though this difference was not statistically different. The average number of packed red blood cell (pRBC) units transfused was not significantly lower in the 24-hour group (2 units) compared to the 72-hour group (3 units). Both groups had similar rates of platelet transfusions, and 2 patients in the 24-hour group had a fresh frozen plasma (FFP) transfusion.
In the 24-hour group, 8/15 patients were discharged by hospital day 3, while no patients in the 72-hour arm were discharged within this time frame (p < 0.001 for the difference between 24-hours of octreotide and 72-hours of octreotide) (Figure 2). No patient in the 72-hour group was discharged before hospital day 4. Complications including infection (1 patient vs 0 patients) and dysphagia (2 patients vs 0 patients) were similar in the 2 groups. One person in the 72- hour group died 22 days after admission due to sepsis that occurred as a result of pneumonia.
Figure 2.
Hospital LOS. Shown is a vertical strip plot illustrating the distribution of days until discharge for each patient in each the 24-hour and 72-hour octreotide group.
Discussion
The results of this study suggest that for the treatment of EVH, a 24-hour infusion of octreotide is associated with similar outcomes to a 72-hour infusion. As might be expected, the longer octreotide infusion period was associated with a longer hospital LOS.
Most previous studies of octreotide focused on comparing octreotide with other vasoactive agents, such as vasopressin and terlipressin.11–14 However, data on the optimal duration of octreotide infusion for the treatment of EVH is limited. An early pharmaceutical-sponsored RCT in 1995 showed that the relative risk (RR) of rebleeding was lower in patients when octreotide infusion was continued for 5-days after EBL compared to patients with EBL alone (RR=0.22).15 However, octreotide was not given prior to endoscopy, which is now part of the standard-of-care. A second pharmaceutical-sponsored multicenter, randomized, double-blind study compared vapreotide (another synthetic somatostatin analogue) to placebo in patients with suspected esophageal or gastric variceal bleeding, which was continued for 5-days after endoscopic treatment (sclerotherapy or EBL).16 Control of bleeding was significantly better with vapreotide (compared to placebo) at the time of endoscopy (69% vs. 54%), at 48-hours (73% vs. 54%), and at day 5 (66% vs 50%). There was no difference in recurrent bleeding after 3 days, duration of hospitalization, or mortality. Notably, the difference in bleeding and survival occurred within the first 6-hours of vapreotide infusion vs. placebo, and then became non-significant suggesting that the effect occurs early on. In a more recent RCT, patients were started on octreotide infusion before endoscopic therapy (band ligation or sclerotherapy) and then octreotide was continued for 2-days vs. 5-days.17 Two days of octreotide infusion were found to be as efficacious as the 5-days of infusion in preventing early rebleed. These data suggest that prolonged infusion of octreotide may be unnecessary.
Importantly, our study demonstrated that shortening the duration of octreotide to 24 hours could have significant clinical – and economic – benefits. A shorter infusion time, in our patients, was not associated with increased re-bleeding events or increased mortality. The need for transfusions was slightly higher in the 24-hour octreotide group compared to the 72-hour octreotide group, but the average number of units transfused per patient was lower; neither of the differences reached statistical significance.
The primary limitation of this trial is that because it was closed early, it is underpowered to inform its primary outcome. Thus, it must be acknowledged that we are unable to make definitive conclusions about the appropriate duration of octreotide. Nonetheless, these results establish proof-of-concept for the use of 24-hour octreotide infusion in patients with EVH after EBL, which may be more appropriate than a 72-hour (or 5 day) octreotide duration of therapy.
In conclusion, our findings suggest that a 24-hour infusion of octreotide may be equally effective for the prevention of re-bleeding in patients with EVH after EBL. Further, the data suggest that a shorter duration of octreotide infusion therapy after EBL leads to a reduced hospital LOS and potentially lower healthcare costs.
Supplementary Material
Table 2.
Clinical presentation
| 72-hr octreotide N=19 | 24-hr octreotide N=15 | |
|---|---|---|
| Presentation | ||
| Hematemesis, n (%) | 16 (84 %) | 10 (67 %) |
| Melena, n (%) | 10 (53 %) | 7 (47 %) |
| Vital signs | ||
| Systolic blood pressure | 114 ± 20 | 115 ± 14 |
| Diastolic blood pressure | 63 ± 14 | 64 ± 13 |
| Heart rate | 95 ± 16 | 93 ± 20 |
| Respiratory rate | 19 ± 3 | 18 ± 3 |
| Vasopressor use | 1 (5 %) | 1 (3 %) |
| Mechanical ventilation > 12 h | 2 (11 %) | 1 (7 %) |
| Nasogastric tube insertion | 2 (11 %) | 0 (0 %) |
| Laboratory data (mean ± SD) | ||
| Hemoglobin (g/dL) | 8.5 ± 2.6 | 8.3 ± 1.4 |
| Hematocrit (%) | 27 ±6 | 25 ± 7 |
| WBC (10^3/μL) | 8.7 ± 5.2 | 5.8 ± 2.4 |
| Platelets (10^3/μL) | 114 ± 78 | 110 ± 55 |
| BUN (mg/dL) | 30 ± 20 | 21 ±12 |
| Creatinine (mg/dL) | 1.0 ± 0.4 | 1.3 ± 1.3 |
| Sodium (mmol/L) | 135 ± 3 | 136 ± 5 |
| Total bilirubin (mg/dL) | 5.0 ± 12.4 | 4.3 ± 5.9 |
| ALT (U/L) | 28 ± 19 | 63 ± 74 |
| AST (U/L) | 59 ± 34 | 111 ± 73 |
| Albumin (g/dL) | 3.1 ± 0.6 | 2.7 ± 0.5 |
| INR | 1.6 ± 0.5 | 1.7 ± 0.7 |
Abbreviations: ALT - alanine aminotransferase; AST - aspartate aminotransferase; BUN - blood urea nitrogen; INR - international ionized ratio; PT - prothrombin time; WBC - white blood cells
Table 3.
Outcomes
| 72-hr octreotide N=19 | 24-hr octreotide N=15 | |
|---|---|---|
| Rebleed | ||
| < 72 | 1 (5 %) | 0 (0 %) |
| > 72 hs | 1 (5 %) | 0 (0 %) |
| Transfusion | ||
| pRBCs | 10 (53 %) | 12 (80 %) |
| Average units transfused | 3 units | 2 units |
| Platelets | 2 (11 %) | 3 (20 %) |
| Average units transfused | 1 unit | 1 unit |
| FFP | 0 (0 %) | 2 (13 %) |
| Average units transfused | − | 2 units |
| Infection | 1 (5 %) | 0 (0 %) |
| Dysphagia/Odynophagia | 2 (11 %) | 0 (0 %) |
| TIPS | 0 (0 %) | 1 (7 %) |
| Hospital length of stay (≤ 3days) | 0 (0 %) | 8 (53 %)* |
| Death | 1 (5 %) | 0 (0 %) |
p<0.001 for 24-hs vs 72-h. All other comparisons between 72- and 24-h octreotide were not statistically significantly different.
Abbreviations: FFP – fresh frozen plasma; TIPS – transjugular intrahepatic portosystemic shunt
Funding
This project was supported, in part, by the National Institutes of Health – the National Institute of Diabetes and Digestive and Kidney Disease and the National Institute of General Medical Sciences (grants P30 DK123704 and P20 GM 130457, respectively, supported DCR).
Footnotes
Conflict of Interest Statement
The following authors declare no conflict of interest of any kind in relationship to the work presented in the above identified manuscript.
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