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Transfusion Strategies for Acute Upper Gastrointestinal Bleeding Trial (2013)

In 2013, Dr. Villanueva et al. randomly assigned over 921 patients with upper gastrointestinal bleed who presented with either hematemesis or melena to either low transfusion goal of >7 threshold or greater transfusion goal of >9 threshold.

Their goal was to assess all-cause mortality in these patients. Patients who received restrictive transfusion showed an almost double reduction in terms of primary outcome (P=0.02) as compared with the liberal group. It’s worthwhile to look at TRISS trial results here that studied the transfusion thresholds in patients with septic shock and found no difference in terms of mortality.

The authors concluded a restrictive strategy significantly improved outcomes in patients with acute upper gastrointestinal bleeding.

Source: NEJM

COLONPREV: FIT vs. colonoscopy for colon cancer screening

2012, FIT vs. colonoscopy for colon cancer screening, NEJM

SUP-ICU: PPI prophylaxis in ICU patients at risk of GI bleed

2018, Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU, NEJM

POP-UP: Pantoprazole or Placebo for Stress Ulcer Prophylaxis

2016, Pantoprazole for reducing GI bleeding in intubated patients, Critical Care Medicine

Albumin in Spontaneous Bacterial Peritonitis

1999, Effect of IV Albumin on Renal Impairment in Patients with Cirrhosis and SBP, NEJM

VALENCE Trial: Sofosbuvir and ribavirin in HCV genotypes 2 and 3

 

2014, Sofosbuvir + ribavirin for HCV, NEJM

Rifaximin and Lactulose for HE trial

 

2013, Rifaximin plus Lactulose in Treatment of Hepatic Encephalopathy, The American Journal of Gastroenterology

Bezafibrate in Primary Biliary Cholangitis

A Placebo-controlled Trial of Bezafibrate in Primary Biliary Cholangitis

Trial Summarized by:
Hajra Munawar, MBBS
Hasan Shafiq, MD

Contribution to literature

This trial revealed that the use of the Bezafibrate (PPAR-a agonist )add-on therapy with ursodeoxycholic acid (UDCA) in patients with primary biliary cholangitis, normalizes the serum levels of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, albumin, and prothrombin index at 24 months.

Description of the trail

The goal of this trial was to compare the Bezafibrate add-on therapy with placebo in patients with primary biliary cholangitis, who had an inadequate response to UDCA, at 24 months and assess the overall difference among complete biochemical markers (AST, ALT, ALP, PT, Total bilirubin and albumin).

Study Design

It was a two-group, randomized, double-blinded, placebo-controlled trial from September 2012 to December 2014, that recruited patients from 21 centers throughout France. Patients were randomly assigned, in a 1:1 ratio, to receive either Bezafibrate 400mg (50 patients) or placebo (50 patients) once daily, patients in both groups received UDCA therapy for 6 months or more and had an inadequate response. Follow up performed every 3 months for 24 months and USG of liver and liver stiffness measurement were performed at baseline, at 12 months and at 24
months.

  • Total number of patients: 100
  • Duration of follow up: 2 years
  • Percentage white female: 95%
  • Mean patient age: 53 years +/- 10
  • Clinically significant pruritus: 40%
  • Fatigue: 58%
  • Advanced stages of disease: 54%

Inclusion criteria:

  • 18 years and older
  • Diagnosed cases of primary biliary cholangitis
  • All patients were treated with UDCA for 6 months or more
  • Inadequate biochemical response (ALP or AST >1.5 times of normal range and abnormal total bilirubin levels) to UDCA.

Exclusion criteria

  • Patients with total bilirubin >3 mg/dl.
  • Patients with autoimmune hepatitis.

Primary outcomes

30 % of the patients with PBC, who had an inadequate response to UDCA, in the bezafibrate group had complete biochemical response ( normal serum levels of ALP, AST, total bilirubin, Albumin, and PT) and 1 % in the placebo group, for a difference of 29% (95% CI,16 to 43; P<0.001) at 24 months.

Secondary Outcomes

  • ALP Levels: At 24 months, 67% in the treatment group and 2 % in the placebo group had normal ALP levels with (95%CI ,47 to 79).
  • Total bilirubin levels: Total bilirubin decreased 14% in the treatment group and increased by 18% in the placebo group.
  • ALP and GGT: 60% median reduction in ALP and GGT in the treatment group at 3 moths.
  • Pruritus and fatigue: Changes in pruritus and fatigue were consistent with the primary outcome
  • Quality of life: No significant change in the quality of life scores.
  • Liver fibrosis: Liver stiffness/fibrosis decreased 15 % in the treatment group and increased by 22% in the placebo group (95% CI, -64 to -8)
  • Histologic data: Histologic data was limited to only 28 patients and no significant difference between the 2 groups.
  • Portal HTN and liver complications: No significant difference in developing Portal HTN and liver complications in 2 groups.

Post hoc outcomes:

  • Total and endogenous bile acids, UDCA and C4 (a marker of bile acid synthesis): no significant difference between the groups
  • IgM, IgG levels, CRP, TNF a, IL12: no significant difference between the groups.

Interpretation (discussion):

The Trial demonstrated that among the patients with primary biliary cholangitis who had an inadequate response to UDCA, approximately one-third of the patients in the bezafibrate group, as compared with no patients in the placebo group, reached the normal levels of biochemical markers at 24 months. Parallel changes with respect to pruritus, fatigue and noninvasive liver fibrosis were
consistent with this result.

Though this trial has some limitations as well. The trial was not large enough or long enough to assess the effect of bezafibrate on hard outcomes, such as liver transplantation and death. Advanced cirrhosis and severe cholestasis should be considered as potential limiting factors for add-on therapy with bezafibrate. Bezafibrate was associated with a 5% increase in the serum creatinine. Stage 3 CKD developed during treatment with bezafibrate in one patient in this trial, who had diabetes and HTN. As a precaution, bezafibrate should be used carefully in patients with diabetes, HTN, or any known kidney disease.

In conclusion, in patients with primary biliary cholangitis, who had an inadequate response to UDCA, add-on therapy with bezafibrate for 24 months resulted in a higher rate of complete biochemical response than UDCA therapy plus placebo. Parallel changes in fatigue, pruritus and liver fibrosis were consistent with this effect. Bezafibrate was associated with an increase in creatinine levels. Longer and larger studies are needed to assess the effects of Bezafibrate on clinical outcome.

Source
Christophe Corpechot, M.D., Olivier Chazouillères, M.D., Alexandra Rousseau, Ph.D., Antonia Le Gruyer, M.D., François Habersetzer, M.D., Ph.D., Philippe Mathurin, M.D., Ph.D., Odile Goria, M.D., Pascal Potier, M.D., Anne Minello, M.D., Ph.D., Christine Silvain, M.D., Armand Abergel, M.D., Ph.D., Maryline Debette-Gratien, M.D., Ph.D., NEJM june 7,2018. Vol. 378 .no.23

Helicobacter Pylori Treatment for the Prevention of Metachronous Gastric Cancer

metachronous gastric cancer, helicobacter pylori

Summarized by / Author: Rohini Manaktala MD (1), Rooma Nankani MD (1)

Summary Reviewer: Paul Robert Anthony Jr. MD (2)

Contribution To Literature:

This trial revealed the beneficial outcome of treating early gastric cancer with H.pylori eradication therapy and the reduction in future development of metachronous gastric cancer compared to placebo.

Description:

The goal of the trial was to determine the incidence of metachronous gastric cancer detected on endoscopy performed at 1-year follow up or later and improvement from baseline in the grade of glandular atrophy in the gastric corpus lesser curvature at the 3 year follow up for individuals with early gastric cancer status post resection and treatment with H.pylori eradication therapy.

Study Design

It was a prospective, single-center, double-blinded, placebo-controlled and randomized trial performed at the National Cancer Center in South Korea that enrolled patients from August 2003 through March 2013.

Patients were randomized in a 1:1 fashion before endoscopic resection to either H.pylori eradication therapy (n = 236) or placebo (n = 234). The treatment group received amoxicillin 1000 mg, clarithromycin 500 mg and proton-pump inhibitor rabeprazole 10 mg which were given twice daily for a week. The placebo group received rabeprazole 10 mg and placebo pills. Both groups received proton-pump inhibitor for additional 4 weeks to promote ulcer healing.

  • Total number of patients: 470
  • Duration of follow-up (endoscopy evaluation): at 3 months, 6 months, 1 year and then every 6 months or 12 months until the last enrolled patient reached the 3 year follow up point
  • Mean patient age: 59 years
  • Percentage male: 75%

Inclusion criteria:

  • Between the ages of 18 and 75 years
  • Histologically confirmed diagnosis of differentiated early gastric cancer or high grade adenoma
  • Endoscopic localization of a mucosal tumor without ulceration and no lymph-node or distant organ metastasis on CT scan
  • Confirmed scheduled endoscopic resection procedure
  • Current H.pylori infection

 

Other salient features/characteristics:

  • The stratification factor for group assignment was the severity of the baseline grade of histologic atrophy at the antrum
  • Paients started the assigned trial medication within 1 week after endoscopic resection
  • Quadruple antibiotic therapy (proton-pump inhibitor, bismuth, metronidazole, tetracycline) was provided for 10 days if H.pylori infection was detected at closeout endoscopic examination

Primary outcomes:

  • The development of metachronous gastric cancer was found to have occurred in 7.2% of the treatment group and in 13.4% of the placebo group (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.26-0.94; P=0.03).
  • The proportion of patients who had an improved grade of atrophy in the corpus lesser curvature was higher in the treatment group than in the placebo group (48.4% vs. 15.0%, P <0.001). The odds ratio for such improvement was 5.30 (95% CI, 3.08 to 9.13) in the treatment group as compared with the placebo group.
  • The proportion of patients who had an improved grade of intestinal metaplasia at the same site was also higher in the treatment group than in the placebo group (36.6% vs. 18.3%, P <0.001). However, no significant difference in grade was found for either glandular atrophy or intestinal metaplasia at the antrum.

Secondary outcomes:

  • Major adverse events included death from any cause which was reported in 11 patients in the treatment group and in 6 in the placebo group (HR, 1.95; 95% CI, 0.72-5.27; P=0.19).
  • Minor adverse events included: taste alteration, nausea, vomiting, diarrhea, abdominal pain, hypersensitivity, dizziness, headache and insomnia. These events were more common in the treatment group than placebo (42.0% vs. 10.2%, P<0.001).

Interpretation:

The trial demonstrated a significant reduction in metachronous gastric cancer development among patients who had received treatment for H.pylori infection than those who had received placebo. This is because persistent inflammation of gastric mucosa from H.pylori infection promotes carcinogenesis and increases tumor growth/invasion. Findings from this trial are in agreement with results from previous systemic reviews and open label trials.  Additionally, this trial found that the proportion of patients with improvement in the grade of gastric corpus atrophy from baseline was significantly higher in the treatment group than placebo at the 3 year follow up.

An advantage of this trial was a longer duration of follow up than previous trials (median follow up 5.9 years versus <3 years). However there are some limitations to the trial which include: (i) disappearance of preventive effect of H.pylori treatment on metachronous cancer after follow up duration of more than 5 years and (ii) exclusion of patients with synchronous gastric cancers that were initially missed but detected within 1 year after treatment. Moreover, in this trial hazard ratio for incidence of metachronous gastric cancer was found to be higher than previous trials which could be explained by the fact that H.pylori eradication was not confirmed and salvage treatment was not given to patients who failed eradication therapy due to the limitation of blinded process.

In conclusion, H.pylori therapy reduces but cannot completely eradicate the risk of metachronous gastric cancer. Also, it was found that H.pylori treatment did not affect the subsequent incidence of gastric adenoma or overall survival.

Choi I., Kook M., Kim Y., et al. Helicobacter Pylori Therapy for the Prevention of Metachronous Gastric Cancer. NEJM. 2018, 378 (12): 1085-1095. Source

 

Authors Affiliation:

1. Department of Internal Medicine, University of Connecticut Health Center

2. Department of Infectious Disease, Saint Francis Hospital, Hartford, Connecticut

 

STOPAH Trial: Prednisolone or Pentoxifylline for Alcoholic Hepatitis

stopah trial on steroids in alcoholic hepatitis

The use of steroids vs Pentoxifylline in severe alcoholic hepatitis has long been debated. The STOPAH trial published in NEJM in 2015 was a strong 2×2 factorial design, randomized trial that established that neither pentoxifylline nor prednisolone provided significant survival benefit in patients with severe alcoholic hepatitis. Take a look at my visual abstract for the trial. You can use it free for educational purposes.

ANNEXA Trial: Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity

Source: NEJM

Association Between Cirrhosis and Stroke in a Nationally Representative Cohort

Contribution by
Leon Averbukh,
Internal Medicine
UConn Health

Source: JAMA Neurology

MODIFY I / II Trials: Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection

Source: NEJM

Intermittent vs Continuous Proton Pump Inhibitor Therapy for High-Risk Bleeding Ulcers

Source: JAMA Internal Medicine

FAMOUS Trial: Famotidine for the prevention of peptic ulcers and esophagitis in patients taking low-dose aspirin

A non-stop pharmaceutical battle…

FAMOUS trial is a Phase III, randomized, double blind, placebo-controlled trial funded by the pharmaceuticals Merck and Astellas and published in 2009. In this study, Taha et al, conclude that famotidine is effective in reducing gastric and duodenal ulcers as well as erosive esophagitis in patients who require daily aspirin intake. As a competitive inhibitor of histamine H2-receptors on the basolateral membrane of parietal cells, Famotidine reduces gastric acid secretion. It was first developed by the Japanese pharmaceutical Yamanouchi/Astellas and posteriorly marketed by Merck as Pepcid.

The study brought the attention of gastroenterologists and pharmaceuticals worldwide. Soon after, on 2010, Fook-Hong et al, demonstrated that Famotidine is inferior to Pantoprazole in preventing recurrence of aspirin-related peptic ulcers or erosions. This clinical trial followed patients for 48 weeks (in contrast to 12-week follow-up in FAMOUS trial) and the authors reported no conflicts of interest. Years before FAMOUS trial was conducted, Taha et al, demonstrated on 1996 that high dose Famotidine reduces the risk of NSAID induced gastric and duodenal ulcers particularly important for patients with arthritis who require long-term NSAID use. A multicenter study that used a protocol similar to the trial by Taha et al, failed to demonstrate the benefits of Famotidine in preventing NSAID-induced gastric ulcers, however, this controversial study was never published as a full paper.

Where at we at, 22 years later?

On 2012, REDUCE trials 1&2 by Laine et al, tested a single-tablet combination of Ibuprofen and Famotidine in prevention of gastric ulcers with a very small, yet statistically significant, benefit for the treatment group. Furthermore, on 2014, Whellan et al , demonstrated that a combined enteric coated aspirin/omeprazole tablet reduces endoscopic gastric ulcers while improving ASA compliance in cardiac patients due to less GI side effects.

On 2018, we count with 2 combination drugs: Duexis (Ibuprofen/Famotidine) approved on 2011, 90 tabs cost $2883.67, and Vimovo (Naproxen/Esomeprazole) approved on 2010, 60 day cost $2473.37.

In conclusion, the work by Taha has opened a Pandora’s box for extensive research that is left to be done, moreover, it has prepared the field for a never ending pharmaceutical battle.

Daniela Guerrero Vinsard MD.
University of Connecticut Health Center.
Department of Internal Medicine.

Source: The Lancet

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