Gastric Varices: Nonselective Beta-Blockers May Lower Mortality
Given the high mortality associated with gastric variceal hemorrhage, ongoing investigation into pharmacologic and interventional approaches remains critical to improving patient outcomes.
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09/24/2025
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by Cara Glynn
Nonselective beta-blockers, a standard therapy for preventing esophageal variceal bleeding in patients with portal hypertension, may also reduce mortality in those with gastric varices.
Gastric varices, a complication of portal hypertension, are less common than esophageal varices but are associated with higher rates of severe bleeding and mortality. Gastric variceal hemorrhage carries a particularly poor prognosis, with mortality rates approaching 45% within three years and rebleeding rates as high as 35% to 90% despite intervention.
Unlike esophageal varices, standardized treatment guidelines for gastric varices remain sparse. Existing approaches including endoscopic band ligation, cyanoacrylate injection, balloon-occluded retrograde transvenous obliteration, and portosystemic shunting are often limited by recurrent bleeding and procedure-related risks, according to Rebecca H. Moon, MD, of the Department of Gastroenterology, Kaiser Permanente Los Angeles Medical Center, and colleagues.
Nonselective beta-blockers (NSBBs) reduce portal hypertension through combined beta-1 and beta-2 blockade, lowering cardiac output and inducing splanchnic vasoconstriction, which decreases portal venous inflow by up to 35%. Additional protective effects, such as reducing bacterial translocation and lowering the incidence of spontaneous bacterial peritonitis, have also been noted. Three primary NSBBs are used clinically: propranolol, nadolol, and carvedilol. While carvedilol exerts a stronger effect by adding alpha-1 blockade, it carries higher risks of hypotension and renal dysfunction in patients with advanced cirrhosis.
Dr. Moon and fellow investigators analyzed data from Kaiser Permanente Southern California, identifying adults aged 18–75 years who were newly diagnosed with gastric varices between 2015 and 2021. Patients with prior splenectomy, transjugular intrahepatic portosystemic shunt (TIPS) procedures, multiple NSBB exposures, or insufficient follow-up were excluded. Participants were followed through February 2022.
The primary outcomes included gastric variceal hemorrhage, esophageal variceal hemorrhage, TIPS placement, liver transplantation, and overall mortality.
The study included 1,276 patients (63% male; mean age, 58.4 years). Nearly half (48%) were Hispanic and 39% White. According to the Sarin Classification, the most common variceal types were GOV1 (29.8%), GOV2 (26.3%), and IGV1 (36.8%).
Comorbidities were frequent, including hypertension (65.9%), obesity (48.5%), and type 2 diabetes (44.7%). More than half of patients had esophageal varices, and 38% had ascites. Major etiologies of liver disease included alcohol use disorder (33%), hepatitis C (21%), and hepatitis B (3%).
During a median follow-up of 1.1 years, 7.1% developed gastric variceal hemorrhage, 21.7% experienced esophageal variceal hemorrhage, 4% required TIPS, 5.3% underwent liver transplantation, and overall mortality was 40%.
Of the 1,276 patients, 767 (62.5%) received NSBB therapy. After adjusting for demographics and comorbidities, NSBB use was significantly associated with lower mortality compared with nonuse (39.2% vs 50.9%; odds ratio [OR] = 0.62; 95% confidence interval [CI] = 0.46–0.84).
No significant differences were observed in rates of gastric variceal hemorrhage, esophageal variceal hemorrhage, TIPS placement, or liver transplantation between users and nonusers. Nadolol was most strongly associated with survival benefit (OR = 0.55), followed by propranolol (OR = 0.71). Outcomes for carvedilol could not be assessed due to small sample size. Median survival from NSBB initiation was 1.4 years.
The authors suggested that the survival benefit of NSBBs in gastric varices may not be mediated solely through bleeding reduction but could also reflect broader protective effects, similar to results seen in the PREDESCI trial, where NSBBs prevented cirrhosis decompensation rather than directly reducing variceal hemorrhage.
The study found higher rates of variceal hemorrhage among Hispanic patients, raising questions about genetic predisposition, metabolic syndrome prevalence, or socioeconomic factors as potential contributors. The authors emphasized the need for further research to explore these disparities.
As a retrospective cohort study, causality cannot be confirmed. Uneven subgroup distribution, underrepresentation of carvedilol, and modest follow-up duration also limit definitive conclusions.
Further prospective studies are needed to clarify the effects of NSBBs on gastric varices and to refine treatment strategies for this high-risk population. Given the high mortality associated with gastric variceal hemorrhage, ongoing investigation into pharmacologic and interventional approaches remains critical to improving patient outcomes, the investigators concluded.
They reported having no conflicts of interest.
Source: Gastro Hep Advances
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The guidelines emphasize four-hour gastric emptying studies over two-hour testing. How do you see this affecting diagnostic workflows in practice?
Dr. Staller: Moving to a four-hour solid-meal scintigraphy will actually simplify decision-making. The two-hour reads miss a meaningful proportion of delayed emptying; standardizing on four hours reduces false negatives and the “maybe gastroparesis” purgatory that leads to repeat testing. Practically, it means closer coordination with nuclear medicine (longer slots, consistent standardized meal), updating order sets to default to a four-hour protocol, and educating front-line teams so patients arrive appropriately prepped. The payoff is fewer equivocal studies and more confident treatment plans.
Metoclopramide and erythromycin are the only agents conditionally recommended for initial therapy. How does this align with what is being currently prescribed?
Dr. Staller: This largely mirrors real-world practice. Metoclopramide remains the only FDA-approved prokinetic for gastroparesis, and short “pulsed” erythromycin courses are familiar to many of us—recognizing tachyphylaxis limits durability. Our recommendation is “conditional” because the underlying evidence is modest and patient responses are heterogeneous, but it formalizes what many clinicians already do: start with metoclopramide (lowest effective dose, limited duration, counsel on neurologic adverse effects) and reserve erythromycin for targeted use (exacerbations, bridging).
Several agents, including domperidone and prucalopride, received recommendations against first-line use. How will that influence discussions with patients who ask about these therapies?
Dr. Staller: Two points I share with patients: evidence and access/safety. For domperidone, the data quality is mixed, and US access is through an FDA IND mechanism; you’re committing patients to EKG monitoring and a non-trivial administrative lift. For prucalopride, the gastroparesis-specific evidence isn’t strong enough yet to justify first-line use. So, our stance is not “never,” it’s just “not first.” If someone fails or cannot tolerate initial therapy, we can revisit these options through shared decision-making, setting expectations about benefit, monitoring, and off-label use. The guideline language helps clinicians have a transparent, evidence-based conversation at the first visit.
The guidelines suggest reserving procedures like G-POEM and gastric electrical stimulation for refractory cases. In your practice, how do you decide when a patient is “refractory” to medical therapy?
Dr. Staller: I define “refractory” with three anchors.
1. Adequate trials of foundational care: dietary optimization and glycemic control; an antiemetic; and at least one prokinetic at appropriate dose/duration (with intolerance documented if stopped early).
2. Persistent, function-limiting symptoms: ongoing nausea/vomiting, weight loss, dehydration, ER visits/hospitalizations, or malnutrition despite the above—ideally tracked with a validated instrument (e.g., GCSI) plus nutritional metrics.
3. Objective correlation: delayed emptying on a standardized 4-hour solid-meal study that aligns with the clinical picture (and medications that slow emptying addressed).
At that point, referral to a center with procedural expertise for G-POEM or consideration of gastric electrical stimulation becomes appropriate, with multidisciplinary evaluation (GI, nutrition, psychology, and, when needed, surgery).
What role do you see dietary modification and glycemic control playing alongside pharmacologic therapy in light of these recommendations?
Dr. Staller: They’re the bedrock. A small-particle, lower-fat, calorie-dense diet—often leaning on nutrient-rich liquids—can meaningfully reduce symptom burden. Partnering with dietitians early pays dividends. For diabetes, tighter glycemic control can improve gastric emptying and symptoms; I explicitly review medications that can slow emptying (e.g., opioids; consider timing/necessity of GLP-1 receptor agonists) and encourage continuous glucose monitor-informed adjustments. Pharmacotherapy sits on top of those pillars; without them, medications will likely underperform.
The guideline notes “considerable unmet need” in gastroparesis treatment. Where do you think future therapies or research are most urgently needed?
Dr. Staller: I see three major areas.
1. Truly durable prokinetics: agents that improve emptying and symptoms over months, with better safety than legacy options (e.g., next-gen motilin/ghrelin agonists, better-studied 5-HT4 strategies).
2. Endotyping and biomarkers: we need to stop treating all gastroparesis as one disease. Clinical, physiologic, and microbiome/omic signatures that predict who benefits from which therapy (drug vs G-POEM vs GES) would transform care.
3. Patient-centered trials: larger, longer RCTs that prioritize validated symptom and quality-of-life outcomes, include nutritional endpoints, and reflect real-world medication confounders.
Our guideline intentionally highlights these gaps to hopefully catalyze better trials and smarter referral pathways.
Dr. Staller is with the Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston.