A Systematic Review and Meta-Analysis on the Role of Somatostatin Therapy in Non-Variceal Gastrointestinal Bleeding

Abstract

Background and Aims: Non-variceal upper gastrointestinal bleeding (NVUGIB) is a common cause of hospitalizations, with proton pump inhibitors (PPIs) being the mainstay treatment. However, there is a lack of high-level evidence to show if adjunctive medical therapy (somatostatin and its analogs) can improve outcomes. This systematic review and meta-analysis aim to evaluate the outcomes of PPIs with adjunctive therapy versus PPI monotherapy in treating NVUGIB in an in-patient setting. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, major databases were systematically searched to retrieve English-only, original studies, published from 1 January 2000 to 31 December 2023, investigating NVUGIB only. The primary outcomes included the mortality rate within 7 days of therapy, rebleeding rate within 7 days of therapy, and length of hospital stay. Results: Seven studies with 789 patients had a pooled mortality rate of 2.0% (95% CI, 0–4.0%), and the pooled risk ratio was 1.11 (95% CI, 0.50–2.48; p = 0.79) between PPI monotherapy and PPIs with adjunctive medical therapy. The pooled rebleeding rate was 13% (95% CI, 6–20%) and the risk ratio was 1.04 (95% CI, 0.73–1.48; p = 0.83). The pooled average length of stay in the hospital was 5.47 days (95% CI, 3.72–7.21 days), with insignificant weighted differences between the two groups. No statistically significant differences were noted in surgical management risk ratios or amount of blood transfusion. Conclusions: Among patients with NVUGIB, adjunctive medical therapy offered no clinical benefits given the statistically insignificant differences in the primary outcomes. However, this conclusion is limited by the considerable variability in treatment protocols, weak control of confounding variables, and missing clinical information in the original studies. Therefore, better-quality, large-scale randomized controlled trials are needed, ideally using standardized somatostatin dosing, timing, delivery routes, and clearly defined inclusion criteria to more accurately evaluate the role of somatostatin in NVUGIB management.

1. Introduction

Acute upper gastrointestinal bleeding (UGIB) is a significant cause of morbidity and mortality, with an annual incidence of approximately 100 cases per 100,000 population [1,2]. Non-variceal upper gastrointestinal bleeds (NVUGIBs), which include conditions such as peptic ulcers, esophagitis, gastritis, mass lesions, arteriovenous malformations, or other erosions, account for approximately 90% of UGIB [3,4]. The mainstay treatment for NVUGIB involves proton pump inhibitors (PPIs), administered after endoscopic stabilization. PPIs reduce rebleeding and mortality rates by decreasing gastric acid and pepsin production, thereby enhancing the stabilization of fibrin clots [3,5]. Peptic ulcer disease (PUD) is one of the most common causes of NVUGIB, with mortality rates for peptic ulcer bleeds consistently ranging between 5% and 10% over the past decade and rebleeding rates between 15% and 35% [6,7].

Somatostatin and its analogs, such as octreotide, are pharmacologic options that promote and preserve blood clot formation by inhibiting gastric acid and pepsin secretion [3,5]. Octreotide already plays a well-established role in the management of variceal bleeds by indirectly causing splanchnic vasoconstriction, thereby reducing portal hypertension [3]. Despite its theoretical benefits and common use in VUGIB, somatostatin and its analogs are not routinely used for NVUGIB due to their high cost and the lack of robust evidence supporting their effectiveness in this context.

Given their potential biological effects, somatostatin and its analogs may hold promise as adjunctive treatments for NVUGIB to improve patient outcomes and reduce complications. However, there has been a lack of recent systematic reviews or meta-analyses to assess the effects of adjunctive medical therapy (somatostatin and its analogs) in NVUGIB [8]. The most recent systematic review and meta-analysis conducted by Goltstein et al. solely determined the outcomes of patients with gastrointestinal angiodysplasias after taking somatostatin analogs, but did not include other etiologies of NVUGIB [9]. Since then, new studies on the outcomes of somatostatin and its analogs for different etiologies of NVUGIB have been published. This systematic review and meta-analysis aim to fill this gap by including new studies and evaluating the effectiveness of PPI monotherapy versus PPIs with adjunctive medical therapy in the management of NVUGIB.

2. Materials and Methods

2.1. Search Strategy

The PubMed, Embase, Web of Science, CINAHL, Google Scholar, and Cochrane databases were systematically searched for all peer-reviewed publications from 1 January 2000 to 31 December 2023 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist [10]. The following keywords were used in all databases: [“upper gastrointestinal bleeding” AND “nonvariceal” AND “somatostatin”]. The full detailed search strategy is available in Supplementary Information Tables S1 and S2. The research protocol was created prior to conducting a formal search strategy. This study, consisting of a systematic review and meta-analysis, was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42023477994; https://www.crd.york.ac.uk/prospero/ (accessed on 20 June 2024)).

2.2. Eligibility Criteria

Relevant articles were independently reviewed by 2 authors (MC, KB). Any discrepancies in the article selection were arbitrated by a third author (KMT). We included studies with outcomes comparing PPI monotherapy to PPIs with adjunctive medical therapy (limited to somatostatin and its analogs only) for patients presenting with NVUGIB while admitted as an inpatient, with active bleeding proximal to the ligament of Treitz, including up to duodenal bleeding. All patients underwent upper endoscopy for evaluation within 48 h of admission and were given either PPI monotherapy or PPIs with adjunctive medical therapy within 24 h. We excluded studies investigating VUGIB, non-somatostatin and its analogs, interventions for NVUGIB, literature reviews/letters/commentaries, case reports/case series, and non-human or cadaver studies.

2.3. Selection Process

The results were exported into an EndNote library for deduplication. Three authors (MC, KMT, KB) independently screened articles and did not know each other’s decisions. All articles first underwent title screening, followed by abstract screening, and finally if deemed relevant, full-text screening (Figure 1). If an article was not included, the exclusion reason was listed.

2.4. Data Extraction

Two authors (MC, KB) extracted data in 2 steps: (1) titles and abstracts and (2) full-text articles. Data from each relevant study was extracted into a standardized form that included: (1) article author; (2) year of publication; (3) study design; (4) quality of study; (5) overall sample size; (6) demographics; (7) primary outcomes (mortality within 7 days of admission, length of hospital stay, rebleeding within 7 days of admission); and (8) secondary outcomes (needing surgical management during index hospitalization, amount of blood transfusions required during index hospitalization).

2.5. Assessment of Bias Risk

The methodological index for non-randomized studies (MINORS) was used to determine the study quality with ratings categorized as “Good”, “Fair”, and “Poor” for non-randomized studies [11]. Cochrane’s risk of bias tool was used to determine the risk of bias for randomized studies [12]. Two reviewers (MC and KB) evaluated the risk of bias and quality of studies. Any disagreements related to quality scores were resolved with the third author (KMT).

2.6. Statistical Analysis

The primary outcome of this study was mortality and rebleeding events, for which we used the risk ratios (RRs) as effect sizes in groups, in which PPI monotherapy and PPIs with adjunctive medical therapy were used across studies included in this review. The RR is the relative measure, showing the proportional change in risk between groups. The hospital length of stay was computed as the weighted mean difference in comparing this outcome among study groups. For studies with reported medians and interquartile ranges, the mean and standard deviation were calculated based on the parametric bootstrap approach (quantile estimation and the Box–Cox method) suggested by McGrath in 2020 [13]. We also calculated the overall event rates of both groups combined. The event or success rate was calculated by dividing the number of patients with reported events by the total sample size of the individual studies. Secondary outcomes included the amount of blood transfusions received and need for surgical management.

The individual estimates of each study were pooled to compute the summary estimates of the clinical outcomes using the restricted maximum likelihood estimation method. A random-effects model accounting for both within– and between–study variance was fit for generating summary estimates. The strength of evidence of heterogeneity across studies was determined by Cochran’s Q and I² statistics [14]. The values of under <30%, 30–60%, 61–75%, and >75% were categorized as low, moderate, substantial, and considerable heterogeneity, respectively [15]. Sensitivity analysis was conducted to determine the validity of the estimated summary effect size. For the sensitivity analysis, a “leave-one-out analysis” was conducted to investigate the impact of the removal of study (1 by 1) on the summary estimates. Publication bias was assessed via doi and funnel plots [16]. All meta-analyses were performed using MetaXL software (v. 5.3; EpiGear International) and SPSS (v. 28). The 95% Clopper–Pearson exact confidence intervals were calculated using R package for overall proportions, whereas Wald-type confidence intervals were used for between-group differences [17,18].

3. Results

3.1. Study Screening

Our systematic search yielded 421 potentially relevant English-language original studies. These were exported and 132 duplicate studies were removed, leaving 289 studies to screen. Of these, 261 studies were excluded, as they were irrelevant to our study’s objectives. The remaining 28 studies advanced to full-text screening, in which 17 studies were excluded for having a wrong study outcome and 4 studies were excluded for having wrong study designs (Figure 1).

3.2. Study Characteristics

Seven studies with 789 patients (PPI monotherapy, n = 396; PPIs with adjunctive medical therapy, n = 393) were included in our meta-analysis [3,5,19,20,21,22,23]. All seven studies were published between 2004 and 2020; all but one study was not investigator-blinded [3]. Three studies were from Greece, two from Korea, one from Iran, and one from the US. There were 500 men and 289 women. The demographics and quality assessment of the included studies are described in

Table 1. Patient demographics and quality ratings of included studies.

Study	Design	Country	Sample Size, N	Age, y (Mean SD *)	Males/ Females, N	Average Hemoglobin on Admission, y (Mean SD *)	Study Quality (MINORS)	Study Quality (Cochrane Risk of Bias)
Nikolopoulou et al., 2004 [23]	Randomized double-blinded placebo- controlled trial	Greece	55	64.4 (16.1)	34/21	9.0 (2)		Low
			55	62.4 (14.1)	32/23	9.2 (1.5)
Riha et al., 2019 [19]	Retrospective cohort study	US	90	62 (median range, 53–69)	58/32	7.6 (median range, 6.1–9.0)	Fair
			90	60 (median range, 53–69)	55/35	6.8 (median range, 5.9–9.2)
Abrishami et al., 2020 [5]	Randomized double-blinded placebo- controlled trial	Iran	58	56 (1.59)	38/20	11.0 (3.1)		Low
			58	55 (1.85)	38/20	11.0 (3.5)
Choi et al., 2011 [3]	Retrospective cohort study	Korea	52	65.4 (19.5)	19/33	8.6 (2.8)	Fair
			49	64.2 (14.2)	32/17	8.3 (2.6)
Avgerinos et al., 2009 [20]	Randomized double-blinded placebo-controlled trial	Greece	14	53.2 (4.9)	11/3	11.5 (0.4)		Low
			14	45.1 (2.8)	13/1	11.3 (0.3)
Tsibouris et al., 2007 [21]	Randomized double-blinded placebo- controlled trial	Greece	82	67.8 (13.1)	60/22	NR		Low
			82	66.4 (13.0)	60/22	NR
Kim et al., 2008 [22]	Retrospective cohort study	Korea	45	60.2 (15.8)	36/9	9.3 (2.7)	Fair
			45	62.4 (15.2)	33/12	9.2 (2.8)

* Except when noted otherwise. NR, not recorded; PPI, proton pump inhibitor; SD, standard deviation.

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Based on the MINORS, three of the included non-randomized studies were rated as “Fair” quality. Based on Cochrane’s risk of bias tool, randomized studies were all rated with a low risk of bias (Table 1). The average hemoglobin on admission was 9.2 (standard deviation [SD], 2.2); with the PPI monotherapy group, the average hemoglobin on admission was 9.5 (SD, 2.2) and the average hemoglobin on admission was 9.3 (SD, 2.2) with the PPIs and adjunctive medical therapy. The etiologies of UGIB included gastric ulcers (35.7% of patients), duodenal ulcers (24.2% of patients), and the rest included other unknown or unspecified etiologies, including 32.8% of patients with shock on admission. Comorbidities included alcohol use (20.5%), smoking (27.1%), congestive heart failure (11.3%), blood thinner use (56.6%), and a history of Helicobacter pylori infection (39.1%). Results and other clinical characteristics are included in

Table 2. Clinical characteristics of included studies.

Study	Treatment Group	Invasive Treatment with Endoscopy, n (%)	Comorbidities	Etiology of Bleed, N	Blood Transfusions Received, Units of pRBCs (Mean SD *)	Shock on Admission, N
Nikolopoulou et al., 2004 [23]	PPI monotherapy	13 (24)	Alcohol user: 7 Smoker: 18 CHF: NR Blood thinner use: 37 History of H. pylori: 36	Gastric ulcer: 22 Duodenal ulcer: 26 Other: 7	3.7 (2.04)	20
	PPIs + octreotide	11 (20)	Alcohol user: 7 Smoker: 14 CHF: NR Blood thinner use: 33 History of H. pylori: 34	Gastric ulcer: 21 Duodenal ulcer: 26 Other: 8	2.5 (2.4)	35
Riha et al., 2019 [19]	PPI monotherapy	37 (41)	Alcohol user: 15 Smoker: NR CHF: 18 Blood thinner use: 89 History of H. pylori: 17	Gastric ulcer: 41 Duodenal ulcer: 38 Other: 11	2.0 (median range, 0–5)	37
	PPIs + octreotide	28 (31)	Alcohol user: 44 Smoker: NR CHF: 17 Blood thinner use: 63 History of H. pylori: 15	Gastric ulcer: 53 Duodenal ulcer: 19 Other: 18	3 (median range, 0–5)	47
Abrishami et al., 2020 [5]	PPI monotherapy	1 (1.72)	Alcohol user: 4 Smoker: 14 CHF: NR Blood thinner use: 34 History of H. pylori: 39	Gastric ulcer: 20 Duodenal ulcer: 27 Other: 10	1.7 (0.5)	NR
	PPIs + octreotide	3 (5.17	Alcohol user: 2 Smoker: 8 CHF: NR Blood thinner use: 43 History of H. pylori: 32	Gastric ulcer: 21 Duodenal ulcer: 26 Other: 11	1.7 (0.5)	NR
Choi et al., 2011 [3]	PPI monotherapy	NR	Alcohol user: NR Smoker: NRCHF: 7 Blood thinner use: 30 History of H. pylori: 14	Gastric ulcer: 27 Duodenal ulcer: 11 Other: 14	NR	26
	PPIs + somatostatin analog	NR	Alcohol user: NR Smoker: NR CHF: 4 Blood thinner use: 23 History of H. pylori: 8	Gastric ulcer: 29 Duodenal ulcer: 8 Other: 12	NR	27
Avgerinos et al., 2009 [20]	PPI monotherapy	NR	Alcohol user: NR Smoker: NR CHF: NR Blood thinner use: NR History of H. pylori: NR	Gastric ulcer: NR Duodenal ulcer: NR Other:	1.0	NR
	PPIs + somatostatin	NR	Alcohol user: NR Smoker: NR CHF: NR Blood thinner use: NR History of H. pylori: NR	Gastric ulcer: NR Duodenal ulcer: NROther:	2.0	NR
Tsibouris et al., 2007 [21]	PPI monotherapy	NR	Alcohol user: 43 Smoker: 82 CHF: 22 Blood thinner use: 57 History of H. pylori: 60	Gastric ulcer: NR Duodenal ulcer: NROther:	3.3 (1.4)	36
	PPIs + somatostatin	NR	Alcohol user: 43 Smoker: 82 CHF: 23 Blood thinner use: 47 History of H. pylori: 60	Gastric ulcer: NR Duodenal ulcer: NROther:	3.2 (1.6)	36
Kim et al., 2008 [22]	PPI monotherapy	NR	Alcohol user: NR Smoker: NR CHF: NR Blood thinner use: 19 History of H. pylori: 16	Gastric ulcer: 29 Duodenal ulcer: 13 Other: 3	3.2 (2.8)	NR
	PPIs + somatostatin	NR	Alcohol user: NR Smoker: NR CHF: NR Blood thinner use: 10 History of H. pylori: 14	Gastric ulcer: 24 Duodenal ulcer: 1 Other: 20	4.5 (4.4)	NR

* Except when noted otherwise. CHF, congestive heart failure; H. pylori, Helicobacter pylori; NR, not recorded; PPI, proton pump inhibitor; pRBCs, packed red blood cells; SD, standard deviation.

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3.3. Meta-Analysis of Primary Outcomes

The pooled mortality rate within 7 days of admission was 2% (95% CI, 0–4.0%; p = 0.02; I² = 62%). When all 789 patients from the seven trials were considered, the pooled RR for mortality between PPI monotherapy and PPIs with adjunctive medical therapy was 1.11 (95% CI, 0.50–2.48; p = 0.79) (Figure 2).

The pooled rebleeding rate within 7 days of admission was 13% (95% CI, 6–20%; p < 0.001; I² = 89%). When patients from six studies (n = 761) were considered (one study did not include rebleeding rates), the pooled RR for rebleeding between PPI monotherapy and PPIs with adjunctive medical therapy was 1.04 (95% CI, 0.73–1.48; p = 0.83) (Figure 3) [3,5,19,21,22,23].

The pooled average length of stay was 5.47 days (95% CI, 3.72–7.21 days; Figure 4), with insignificant weighted differences between the two groups (−0.01; 95% CI, −0.63 to 0.62; p = 0.98) (Figure 5).

3.4. Meta-Analysis of Secondary Outcomes

Secondary outcomes were computed by comparing the PPI monotherapy and PPIs with adjunctive medical therapy groups in two different outcomes: (1) the need for emergency surgical management for definite control of hemorrhage and (2) the amount for blood transfusion after treatment. There were no statistically significant differences noted in surgical management rates during hospitalization (0.98; 95% CI, 0.60–1.59; p = 0.92, Figure 6) or amount of blood transfusion during hospitalization (−0.05; 95% CI, −0.32 to 0.21; p = 0.69, Figure 7) between either group when comparing the pooled RRs.

3.5. Publication Bias

Publication bias was assessed via the visual inspection of doi and funnel plots. To assess if any study involved in the main analysis had a dominant effect, a leave-one-out analysis was conducted. Upon the removal of each study one by one, no significant impact on the summary statistics of the main outcome or heterogeneity was found (Supplementary Information Figures S1 and S2).

4. Discussion

In our meta-analysis, we showed no statistical difference in the primary outcomes of mortality within 7 days of therapy, rebleeding rates within 7 days of therapy, or the length of hospital stay between PPI monotherapy and PPIs with adjunctive medical therapy (somatostatin and its analogs). Furthermore, the rate of surgical management and the amount of blood transfusions during index hospitalization were also not statistically significant between the two groups. As such, we infer that the use of adjunctive medical therapy in NVUGIB is not superior to that of PPI monotherapy and has no additional clinical benefit. It is important to note that other outcomes that were not evaluated in this particular study, such as cessation of bleeding during index endoscopy and the need for other hemostatic techniques (i.e., angiography and embolization), may also help in determining the clinical benefits of adjunctive medical therapy in NVUGIB.

The aim of medical management for VUGIB is to reduce the splanchnic blood flow and portal pressures [24]. Terlipressin, vasopressin, and somatostatin analogs (octreotide and vapreotide) are commonly used vasoactive agents to reduce the splanchnic blood flow. They cause splanchnic vasoconstriction by inhibiting the release of vasodilator glucagon and also via a local mesenteric vasoconstrictive effect that leads to reduced variceal bleeding [25]. Due to the difference in the underlying etiology, NVUGIB may not be associated with elevated intra-variceal pressure. Consequently, reducing the splanchnic blood flow using vasoactive agents such as octreotide may not be effective in controlling NVUGIB.

A recent American Gastroenterological Association (AGA) practice review does not recommend the empirical use of octreotide for the treatment of NVUGIB; however, a low threshold for octreotide use is recommended in cases where portal hypertension is suspected [26]. Additionally, the use of octreotide may be associated with adverse events such as diarrhea, abdominal pain, flatulence, steatorrhea, vomiting, cholelithiasis, biliary sludge, sinus bradycardia, and arrhythmias [27]. Hence, considering the lack of demonstrated efficacy of octreotide for the treatment of NVUGIB and the risk of potential adverse events, octreotide is not recommended as an adjuvant treatment for NVUGIB.

In a systematic review and meta-analysis conducted by Goltstein et al., they found that somatostatin analog therapy was safe and effective for patients with gastrointestinal angiodysplasias requiring transfusion [9]. This was an interesting finding given AGA’s recommendation of not starting octreotide for NVUGIB. Their findings also did not agree with our findings. However, our study included all etiologies of NVUGIB, with gastric and duodenal ulcers being the most prevalent, while their study only included NVUGIB with gastrointestinal angiodysplasia.

In addition, there were differences in design between studies, which could have contributed to the non-statistically significant results. It is important to note that in our analysis, one study contributed disproportionately to the overall effect size, accounting for nearly 50% of the weight in certain pooled outcomes due to its larger sample size. Although the leave-one-out sensitivity analysis showed minimal impact on the overall estimates when this study was excluded, the limited number of studies in the meta-analysis amplifies the influence of any single study. Therefore, the dominance of that study must be interpreted with caution, as it could obscure or amplify treatment effects, and we consider this a notable limitation of the evidence synthesis [19].

Some studies, such as those by Nikolopoulou et al., included participants who received endoscopy followed by octreotide followed by PPIs [23]. Alternatively, in studies by Choi et al. and Kim et al., octreotide or analog infusion were given following a PPI bolus [3,22]. In Abrishami et al., patients were given PPIs every 12 h during their hospitalization and were given subcutaneous octreotide prior to endoscopy, and the time lag afterwards was not reported. As PPI and octreotide dosing were not reported, it is possible that patients could have received the medications up to 11 h apart, perhaps not lending as much theoretical pH control [5]. While many of the included studies separated patients into groups receiving both PPIs and octreotide, others such as Tsibouris et al. had each cohort only receive one type of infusion [21].

In Abrishami et al., the time between PPI and octreotide dosing was not controlled, thus there may be differences in dose timing [5]. Some studies used a higher dose of octreotide, 500 micrograms per hour, versus the standard practice of 250 micrograms per hour, perhaps leading to a more potent effect. In Avgerinos et al., participants were initiated on saline, followed by somatostatin or pantoprazole infusion, then given saline, and somatostatin or pantoprazole injection immediately after, which may confound the sequential importance of dosing order [20]. Furthermore, if PPIs are given first, there may already be an overall increased pH, leading to somatostatin appearing less potent [21]. Additionally, some methodologies included endoscopic hemostasis via clipping devices prior to PPIs or octreotide, perhaps leading to a falsely low significance value in its actual efficacy or adding further pH variability related to anesthetics for the procedure [3]. Also, apart from Tsibouris et al., those who received endoscopic treatment generally did not have a standardized means of hemostasis or a standardized performing endoscopist [21]. Perhaps the method of hemostasis or experience of practitioner confounded the overall risk of rebleeding. Our results show that there was no consistency regarding which group (PPI monotherapy compared to PPIs with somatostatin or its analogs) had more patients undergoing invasive treatment with endoscopy following treatment. Although it was not feasible for subgroup analysis to give a definitive conclusion on the impact of endoscopic hemostasis in the context of our study, this finding may be a signaling result to consider that not giving somatostatin and its analogs does not predispose patients to increased risk of bleeding requiring endoscopic hemostasis.

Furthermore, in all studies, no severe adverse events were related to the administration of octreotide itself, or interactions when receiving PPIs [3,5,21]. There were reported deaths related to rebleeding, including three deaths confounded by advanced age (patients in their 80s) and six deaths following emergent surgery with hemodynamic instability [22,23].

However, there are notable limitations to our study, most importantly the substantial clinical heterogeneity in the treatment methodology among the included trials. Specifically, the studies differed in the order in which PPIs and somatostatin analogs were administered, the timing between doses, and the route and dosage of somatostatin (e.g., subcutaneous injection vs. intravenous infusion, standard vs. high doses). In several studies, the drugs were given hours apart or the sequence of administration was not clearly reported, which could impact drug synergy and clinical effectiveness. Additionally, the timing relative to endoscopy varied, with some patients receiving pharmacologic treatment before and others after the procedure. Such variability likely introduced confounding factors that may have influenced treatment outcomes, either underestimating or overestimating the efficacy of adjunctive therapy. This heterogeneity limits the strength and generalizability of our conclusions.

The timing of drug administration represents another important limitation of this study. Across the included trials, there was no consistent control over when PPIs and somatostatin analogs were initiated relative to diagnostic or therapeutic endoscopy. In some studies, the drugs were given prior to endoscopy, while in others, they were administered after the procedure. This inconsistency in timing is critical, as the effectiveness of acid suppression and vasoactive therapies is time-sensitive; earlier administration may enhance clot stability and reduce active bleeding. The inability to account for or standardize drug timing across studies contributes to methodological heterogeneity and may have obscured the true impact of adjunctive treatment. Future studies should incorporate uniform protocols specifying the timing of drug initiation, especially in relation to endoscopic evaluation, to allow for more accurate comparisons of clinical outcomes.

Also, the number of days of index hospitalization in which patients received therapy (PPI monotherapy vs. PPIs and adjunctive medical therapy) varied among studies. However, we only included studies in which patients received therapy during hospitalization. All studies included patients with NVUGIB at a site above the ligament of Treitz; however, a few studies included duodenal bleeds, while other studies only included NVUGIB proximal to the pylorus [21,22]. Given that bleeding from the duodenum may be more difficult to manage, the results could be skewed against using adjunctive therapy in NVUGIB. Angiography and embolization are increasingly being used to control bleeding instead of for emergent surgical management. We did not specifically look at those two techniques, which could limit our findings regarding applicability in daily clinical practice. Future research should implement standardized protocols for drug administration, dosing, and timing to enable more reliable assessments of the therapeutic value of somatostatin analogs in NVUGIB management.

Another key limitation is the potential for confounding by baseline patient characteristics. Across the included studies, patients varied significantly in clinical status: some presented with hemodynamic instability (shock), others were taking anticoagulants or antiplatelet agents, and some had confirmed H. pylori infection, while others did not. These factors are known to influence outcomes such as rebleeding and mortality, but due to inconsistent or incomplete reporting, we were unable to perform adjusted analyses or stratify patients by these variables. As a result, our pooled estimates may reflect uncontrolled confounding. Moreover, in the non-randomized studies, treatment allocation was not clearly described, and it is possible that sicker patients were more likely to receive somatostatin along with PPIs, introducing selection bias. This could artificially attenuate or exaggerate the observed effects of adjunctive therapy, limiting the internal validity of our findings, which highlights the need for future randomized studies with rigorous control for baseline confounders.

Additionally, except for PUD (which was noted in 50% of patients), other etiologies of NVUGIB were not specified in the included studies. We were not able to delineate by the specific etiology of NVUGIB (i.e., arteriovenous malformations, malignancy) if adjunctive therapy would be beneficial for those specific etiologies, which can limit applicability in daily clinical practice. Furthermore, there were no set variables or characteristics for included or excluded participants, nor those who would receive treatment with adjunctive medical therapy, and there was no set scale or definition for the description of rebleeding associated with adjunctive medical therapy use. As some studies excluded individuals with hemodynamic instability related to gastrointestinal bleeding, it is possible that its utility in severe gastrointestinal bleeds was not fully evaluated [20].

Additionally, the reporting of outcomes was incomplete in some studies, with critical details such as the timing of adjunctive medical therapy administration, therapy duration, and specific endoscopic hemostasis techniques often missing. A further limitation of our study is the incomplete reporting of adverse events related to somatostatin and its analogs in the included trials. Although some studies noted that no severe adverse events occurred, they generally did not provide detailed data on non-serious side effects such as gastrointestinal discomfort, bradycardia, cholelithiasis, or metabolic disturbances, which are known potential complications of somatostatin use. Without consistent and quantitative reporting of adverse events, including type, frequency, and severity, it is not possible to fully assess the safety profile of adjunctive therapy. This lack of data limits our ability to draw definitive conclusions about the risk-to-benefit ratio of somatostatin in NVUGIB. Future trials should include systematic adverse event monitoring and transparent reporting to better inform clinical risk assessments. Variations in the expertise and type of endoscopic hemostasis techniques used in the studies could also have confounded the results, potentially masking any effects of adjunctive medical therapy. Geographic biases were also evident, with most studies conducted in specific regions (Greece, Korea, Iran, and the US), which may limit the generalizability of findings to broader populations. These limitations underscore the need for standardized protocols, consistent definitions, and high-quality randomized controlled trials to better evaluate octreotide’s role in NVUGIB management.

Additionally, none of the included studies reported outcomes stratified by intensive care unit (ICU) admission status or need for vasopressor support. These clinical indicators are important markers of illness severity and may modify the response to adjunctive therapy. It is plausible that patients in shock or those requiring intensive care support could benefit more from somatostatin-based therapy due to its effects on the splanchnic blood flow and hemodynamic stability. However, without subgroup analysis based on ICU admission or vasopressor use, we were unable to explore this hypothesis. Authors acknowledge this as a further limitation and suggest it as a focus for future prospective studies.

In addition, the included studies varied in how they reported the underlying causes of NVUGIB. While PUD accounted for approximately 50% of patients, other etiologies such as angiodysplasias were either grouped into broader categories or not separately reported. Given that somatostatin analogs may have particular benefit in vascular lesions such as angiodysplasias, this lack of etiological specificity limited our ability to conduct meaningful subgroup analyses. Separate analysis of peptic ulcer-related bleeding versus non-ulcer etiologies (including angiodysplasia) was not feasible due to insufficiently stratified data across studies. Therefore, future trials and meta-analyses to clearly report and analyze outcomes by etiology to better understand the potential role of somatostatin therapy across distinct NVUGIB subtypes are recommended.

Next, another limitation is the absence of meta-regression, which could have explored whether differences in dosage, timing, or route of drug administration moderated the effects observed. Given the variability in intervention protocols among the included studies, meta-regression would have added important nuance to understanding heterogeneity. However, due to the relatively small number of studies (n = 7), we did not perform meta-regression, as its statistical power is limited in small samples and can yield unreliable or spurious associations. As noted by Thompson and Higgins, meta-regression should generally be avoided unless at least 10 studies are included in the analysis [28].

Additionally, we did not perform a subgroup analysis based on study design or methodological quality. This omission was due to the limited number of studies, which precluded meaningful statistical comparisons between design types. However, we recognize that mixing study designs may increase the risk of bias and heterogeneity in the pooled estimates. Future meta-analyses that include a greater number of studies should incorporate stratified analyses by study type to assess the robustness of findings and better understand how study design influences the observed outcomes.

Also, most included studies did not report bleeding severity using standardized clinical tools, such as the Forrest classification, Rockall score, or other validated scales. As a result, we were unable to stratify or adjust our meta-analysis based on the severity of bleeding at presentation. This limitation may have masked a potential benefit of adjunctive somatostatin therapy in high-risk or severely bleeding patients, as the pooled analysis treats all patients as a homogeneous population. This highlights the need for future studies to include and stratify by validated bleeding severity scores.

Future meta-analyses that include a greater number of studies should incorporate stratified analyses by study type to assess the robustness of findings and better understand how study design influences the observed outcomes.

Another important limitation is the absence of a formal GRADE (Grading of Recommendations Assessment, Development, and Evaluation) assessment. Several included studies lacked adequate detail for assessing precision, consistency, and indirectness, which are the key domains within the GRADE framework, making standardized grading difficult and potentially subjective [29,30]. Although we employed validated tools such as the Cochrane RoB 2 and MINORS to assess study quality, we acknowledge that the omission of GRADE limits our ability to fully communicate the overall certainty of the evidence. Therefore, future systematic reviews on this topic should consider incorporating both meta-regression and GRADE to enhance transparency and evidence synthesis.

5. Conclusions

Among patients with NVUGIB, adjunctive medical therapy offered no clinical benefits given the statistically insignificant differences in primary outcomes. However, this conclusion is limited by the considerable variability in treatment protocols, weak control of confounding variables, and missing clinical information in the original studies. Notably, differences in patient characteristics (e.g., shock status, anticoagulant use, H. pylori infection) and lack of uniform dosing and timing protocols further restrict our ability to draw definitive conclusions. Therefore, while the current evidence does not support the routine use of adjunctive therapy, we refrain from making broad generalizations that PPI monotherapy is universally sufficient for all NVUGIB cases. Instead, we emphasize that better-quality, large-scale randomized controlled trials are needed, ideally using standardized somatostatin dosing, timing, delivery routes, and clearly defined inclusion criteria to more accurately evaluate the role of somatostatin in NVUGIB management.

Somatostatin and its analogs are significantly more expensive than standard PPI therapy. Given our finding that adjunctive therapy offered no added clinical benefit, the financial implications are considerable for both healthcare institutions and patients. This underscores the need for future cost-effectiveness analyses to evaluate whether somatostatin use in NVUGIB is justified based on health outcomes and economic impact. Furthermore, we recognize the value of developing clinical decision algorithms or flowcharts to help guide the use of adjunctive therapy in real-world settings. While the current evidence is insufficient to construct such a tool with high confidence, this represents a meaningful area for future work that could improve clinical decision-making and optimize resource utilization.

Also, PPI monotherapy may be sufficient in patients with NVUGIB related to peptic ulcer bleeding, but further studies are required on other causes of bleeding, such as arteriovenous malformations, angioectasias, and Dieulafoy’s lesions. Given that prior studies have only shown the outcomes of somatostatin analogs for angiodysplasia-related bleeding, future research should focus on standardized, high-quality studies to evaluate the timing, dosing, and delivery route of somatostatin analogs, particularly for different subgroups or etiologies of NVUGIB where it might be beneficial. Investigating safety profiles and protocols for patient selection in high-risk populations is also warranted. Until such evidence emerges, PPI monotherapy remains the cornerstone of NVUGIB management.