Gastroenterology

Gastroesophageal disorders

ASTRONAUT trial: Omeprazole for PUD

Article Name: A Comparison of Omeprazole with Ranitidine for Ulcers Associated with Nonsteroidal Antiinflammatory Drugs

URL: https://www.nejm.org/doi/full/10.1056/nejm199803123381104

Journal and year of publication: NEJM, 1998

Trial Design: Randomized controlled trial

Population: 541 patients
Key inclusion criteria:
– Requiring continuous therapy with NSAIDs above specified therapeutic doses, and not more than 10 mg of prednisolone or its equivalent per day
– Ulcers present on endoscopy
Key exclusion criteria:
– Concurrent erosive or ulcerative esophagitis
– Pyloric stenosis
– GI bleeding

Intervention Studied: Omeprazole

Control: Ranitidine

Outcomes:
– Treatment success at weeks (improvement of symptoms and ulcers on endoscopy): Omeprazole 20 mg: 80%. vs Omeprazole 40 mg: 79% vs Ranitidine: 63% (P<0.001 for the comparison with 20 mg of omeprazole; P = 0.001 for the comparison with 40 mg of omeprazole)

The authors concluded that “In patients who use NSAIDs regularly, omeprazole healed and prevented ulcers more effectively than did ranitidine.“

Citation: _{Yeomans ND, Tulassay Z, Juhász L, Rácz I, Howard JM, van Rensburg CJ, Swannell AJ, Hawkey CJ. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group. N Engl J Med. 1998 Mar 12;338(11):719-26. doi: 10.1056/NEJM199803123381104. PMID: 9494148.}

Endoscopy timing for UGI bleeds

Article Name: Timing of Endoscopy for Acute Upper Gastrointestinal Bleeding

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1912484

Journal and year of publication: NEJM, 2020

Trial Design: Randomized controlled trial

Population: 516 patients
Key inclusion criteria:
– Overt signs of acute upper GI bleeding (hematemesis, melena, or both)
– Predicted to be at high risk for further bleeding or death on the basis of a Glasgow–Blatchford score of 12 or higher
Key exclusion criteria:
– Patients with hypotensive shock or whose condition did not stabilize after initial resuscitation

Intervention Studied: Endoscopy within 6 hours (urgent-endoscopy group) after gastroenterologic consultation

Control: Endoscopy between 6 and 24 hours (early-endoscopy group) after gastroenterologic consultation

Outcomes:
– The 30-day mortality: Urgent-endoscopy: 8.9% vs Early-endoscopy: 6.6%.
Difference: 2.3% (95%CI: −2.3 to 6.9)
– Further bleeding within 30 days: Urgent-endoscopy: 10.9% vs Early-endoscopy: 7.8%. Difference: 3.1% (95%CI: −1.9 to 8.1)

The authors concluded that ” In patients with acute upper gastrointestinal bleeding who were at high risk for further bleeding or death, endoscopy performed within 6 hours after gastroenterologic consultation was not associated with lower 30-day mortality than endoscopy performed between 6 and 24 hours after consultation.“

Citation: _{Lau JYW, Yu Y, Tang RSY, Chan HCH, Yip HC, Chan SM, Luk SWY, Wong SH, Lau LHS, Lui RN, Chan TT, Mak JWY, Chan FKL, Sung JJY. Timing of Endoscopy for Acute Upper Gastrointestinal Bleeding. N Engl J Med. 2020 Apr 2;382(14):1299-1308. doi: 10.1056/NEJMoa1912484. PMID: 32242355.}

IV PPIs for UGI bleed

Article Name: Effect of Intravenous Omeprazole on Recurrent Bleeding after Endoscopic Treatment of Bleeding Peptic Ulcers

URL: https://www.nejm.org/doi/full/10.1056/NEJM200008033430501

Journal and year of publication: NEJM, 2000

Trial Design: Randomized, placebo-controlled trial

Population: 240 patients
Key inclusion criteria:
– Successful endoscopic treatment of actively bleeding ulcers or ulcers with nonbleeding visible vessels
Key exclusion criteria:
– Patients in whom endoscopic treatment was unsuccessful

Intervention Studied: Omeprazole IV for 72 hours + Omeprazole 20 mg for 8 weeks

Control: Placebo + Omeprazole 20 mg for 8 weeks

Outcomes:
– Bleeding recurrence (within 30 days): Omeprazole group: 6.7% vs Placebo group: 22.5% (P<0.001)
– Death (within 30 days): Omeprazole group: 4.2% vs Placebo group: 10% (P=0.13)

The authors concluded that “After endoscopic treatment of bleeding peptic ulcers, a high-dose infusion of omeprazole substantially reduces the risk of recurrent bleeding.“

Citation: _{Lau JY, Sung JJ, Lee KK, Yung MY, Wong SK, Wu JC, Chan FK, Ng EK, You JH, Lee CW, Chan AC, Chung SC. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. N Engl J Med. 2000 Aug 3;343(5):310-6. doi: 10.1056/NEJM200008033430501. PMID: 10922420.}

Transfusions for UGI bleed

Article Name: Transfusion Strategies for Acute Upper Gastrointestinal Bleeding

URL: https://www.nejm.org/doi/full/10.1056/nejmoa1211801

Journal and year of publication: NEJM, 2013

Trial Design: Randomized controlled trial

Population: 921 patients
Key inclusion criteria:
– Hematemesis (or bloody nasogastric aspirate), melena, or both
Key exclusion criteria:
– Massive exsanguinating bleeding
– Acute coronary syndrome
– Lower gastrointestinal bleeding

Intervention Studied: Restrictive strategy (transfusion if hemoglobin <7 g/dL)
per deciliter)

Control: Liberal strategy (transfusion if hemoglobin <9 g/dL)

Outcomes:
– Percentage of patients who didn’t receive transfusion: Restrictive strategy: 51% vs Liberal strategy: 14% (P<0.001)
– Probability of survival (at 6 weeks): Restrictive strategy: 95% vs Liberal strategy: 91% (P=0.02)
– Occurrence of further bleeding: Restrictive strategy: 10% vs Liberal strategy: 16% (P=0.01)
– Adverse events occurrence: Restrictive strategy: 40% vs Liberal strategy: 48% (P=0.02)

The authors concluded that “As compared with a liberal transfusion strategy, a restrictive strategy significantly improved outcomes in patients with acute upper gastrointestinal bleeding.“

Citation: _{Villanueva C, Colomo A, Bosch A, Concepción M, Hernandez-Gea V, Aracil C, Graupera I, Poca M, Alvarez-Urturi C, Gordillo J, Guarner-Argente C, Santaló M, Muñiz E, Guarner C. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013 Jan 3;368(1):11-21. doi: 10.1056/NEJMoa1211801. Erratum in: N Engl J Med. 2013 Jun 13;368(24):2341. PMID: 23281973.}

Ceftriaxone for SBP prophylaxis in UGI bleed

Article Name: Norfloxacin vs Ceftriaxone in the Prophylaxis of Infections in Patients With Advanced Cirrhosis and Hemorrhage

URL: https://www.gastrojournal.org/article/S0016-5085(06)01535-6/fulltext

Journal and year of publication: Gastroenterology, 2006

Trial Design: Randomized controlled trial

Population: 111 patients
Key inclusion criteria:
– Hematemesis and/or melena within 24 hours prior to inclusion
– Advanced cirrhosis
Key exclusion criteria:
– Presence of signs of infection
– Antibiotics within 2 weeks before the hemorrhage
– HIV infection

Intervention Studied: Intravenous Ceftriaxone

Control: Oral norfloxacin

Outcomes:
– Probability of developing infections: Was significantly higher in patients receiving norfloxacin:
– Proved or possible infections: 33% vs 11%, P = .003
– Proved infections: 26% vs 11%, P = .03
– Spontaneous bacteremia or spontaneous bacterial peritonitis: 12% vs 2%, P = .03

The authors concluded that “Intravenous ceftriaxone is more effective than oral norfloxacin in the prophylaxis of bacterial infections in patients with advanced cirrhosis and hemorrhage.“

Citation: _{Fernández J, Ruiz del Arbol L, Gómez C, Durandez R, Serradilla R, Guarner C, Planas R, Arroyo V, Navasa M. Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage. Gastroenterology. 2006 Oct;131(4):1049-56; quiz 1285. doi: 10.1053/j.gastro.2006.07.010. PMID: 17030175.}

Intestinal disorders

SONIC trial: Infliximab for Crohn’s disease

Article Name: Infliximab, Azathioprine, or Combination Therapy for Crohn’s Disease

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa0904492

Journal and year of publication: NEJM, 2010

Trial Design: Randomized controlled trial

Population: 508 patients
Key inclusion criteria:
– At least 21 years of age
– Crohn’s disease for at least 6 weeks
– Corticosteroid-dependent
Key exclusion criteria:
– Had short bowel syndrome, ostomy, a symptomatic stricture, or abscess
– Recent abdominal surgery (within 6 months)
– Multiple sclerosis or cancer

Intervention Studied:
1) Infliximab monotherapy
2) Azathioprine monotherapy
3) Infliximab + Azathioprine

Control: See above

Outcomes:
– Corticosteroid-free clinical remission (at 26 weeks):
– Combination therapy: 56.8% of patients vs Infliximab monotherapy: 44.4% of patients (P=0.02)
– Azathioprine monotherapy: 30.0% of patients (P<0.001 for the comparison with combination therapy; P=0.006 for the comparison with infliximab)
– Development of serious infections: Combination therapy: 3.9% of patients. Infliximab monotherapy: 4.9% of patients. Azathioprine monotherapy: 5.6% of patients

The authors concluded that “Patients with moderate-to-severe Crohn’s disease who were treated with infliximab plus azathioprine or infliximab monotherapy were more likely to have a corticosteroid-free clinical remission than those receiving azathioprine monotherapy.“

Citation: _{Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, Lichtiger S, D’Haens G, Diamond RH, Broussard DL, Tang KL, van der Woude CJ, Rutgeerts P; SONIC Study Group. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010 Apr 15;362(15):1383-95. doi: 10.1056/NEJMoa0904492. PMID: 20393175.}

Adalimumab for Crohn’s disease

Article Name: Adalimumab Induction Therapy for Crohn Disease Previously Treated with Infliximab

URL: https://www.acpjournals.org/doi/10.7326/0003-4819-146-12-200706190-00159

Journal and year of publication: Annals of Internal Medicine, 2007

Trial Design: Randomized controlled trial

Population: 325 patients
Key inclusion criteria:
– Crohn disease for at least 4 months, moderately to severely at baseline
– Intolerant to infliximab or have previously responded to it and lost response
Key exclusion criteria:
– Primary nonresponse to infliximab
– Received infliximab or another TNF antagonist within 8 weeks

Intervention Studied: Adalimumab

Control: Placebo

Outcomes:
– Achieved remission (at 4 weeks): Adalimumab: 21% of patients vs Placebo: 7%
(P < 0.001)
– Discontinuation of therapy due to adverse events: Adalimumab: 2 out 159 of patients vs Placebo: 4 out 166 patients
– Serious infections: Adalimumab: 0 patients vs Placebo: 4 out 166 patients

The authors concluded that “Adalimumab induces remissions more frequently than placebo in adult patients with Crohn disease who cannot tolerate infliximab or have symptoms despite receiving infliximab therapy.“

Citation: _{Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Colombel JF, Panaccione R, D’Haens G, Li J, Rosenfeld MR, Kent JD, Pollack PF. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med. 2007 Jun 19;146(12):829-38. doi: 10.7326/0003-4819-146-12-200706190-00159. Epub 2007 Apr 30. PMID: 17470824.}

UNITI trial: Ustekinumab for Crohn’s disease

Article Name: Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease

URL: https://www.nejm.org/doi/full/10.1056/nejmoa1602773

Journal and year of publication: NEJM, 2016

Trial Design: Randomized controlled trial

Population: UNITI-1 trial: 741 patients + UNITI-2 trial: 628 patients
Key inclusion criteria:
– Crohn’s disease for at least 3 months, with moderate to severe disease
– Failure of prior immunosuppressive medications
Key exclusion criteria:
– Infections (including active tuberculosis)
– History of cancer

Intervention Studied: Single intravenous dose of ustekinumab (130 mg OR 6 mg/kg)

Control: Placebo

Outcomes:
– Response rates (at week 6):
– UNITI-1 Trial: Ustekinumab: (at 130 mg: 34.3%) (at 6 mg/kg: 33.7%) vs Placebo: 21.5% (P≤0.003 for both comparisons with placebo)
– UNITI-2 Trial: Ustekinumab: (at 130 mg: 51.7%) (at 6 mg/kg: 55.5%) vs Placebo: 28.7% (P<0.001 for both comparisons with placebo)

The authors concluded that “Among patients with moderately to severely active Crohn’s disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy.“

Citation: _{Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR, Blank MA, Johanns J, Gao LL, Miao Y, Adedokun OJ, Sands BE, Hanauer SB, Vermeire S, Targan S, Ghosh S, de Villiers WJ, Colombel JF, Tulassay Z, Seidler U, Salzberg BA, Desreumaux P, Lee SD, Loftus EV Jr, Dieleman LA, Katz S, Rutgeerts P; UNITI–IM-UNITI Study Group. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med. 2016 Nov 17;375(20):1946-1960. doi: 10.1056/NEJMoa1602773. PMID: 27959607.}

ACT trial: Infliximab for Ulcerative Colitis

Article Name: Infliximab for Induction and Maintenance Therapy for Ulcerative Colitis

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa050516

Journal and year of publication: NEJM, 2005

Trial Design: Randomized controlled trial

Population: ACT1 Trail: 364 patients, Act 2 Trail: 364 patients
Key inclusion criteria:
– Established diagnosis of ulcerative colitis.
– Mayo score 6 to 12 and moderate-to-severe active disease on sigmoidoscopy despite being on immunotherapy
Key exclusion criteria:
– Positive tuberculin skin tests with the use of purified protein derivative
– Indeterminate colitis, Crohn’s disease, or clinical findings suggestive of Crohn’s disease

Intervention Studied: Infliximab

Control: Placebo

Outcomes:
– Percentage of patients with clinical response (at 8 weeks):
– In ACT 1 Trial: Infliximab 5 mg: 69% vs Infliximab 10 mg: 61% vs Placebo: 37% (P<0.001 for both comparisons with placebo)
– In ACT 2 Trial: Infliximab 5 mg: 64% vs Infliximab 10 mg: 69% vs Placebo: 29% (P<0.001 for both comparisons with placebo)

The authors concluded that “Patients with moderate-to-severe active ulcerative colitis treated with infliximab at weeks 0, 2, and 6 and every eight weeks thereafter were more likely to have a clinical response at weeks 8, 30, and 54 than were those receiving placebo.“

Citation: _{Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, Travers S, Rachmilewitz D, Hanauer SB, Lichtenstein GR, de Villiers WJ, Present D, Sands BE, Colombel JF. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005 Dec 8;353(23):2462-76. doi: 10.1056/NEJMoa050516. Erratum in: N Engl J Med. 2006 May 18;354(20):2200. PMID: 16339095.}

Vancomycin for C. diff colitis

Article Name: A Comparison of Vancomycin and Metronidazole for the Treatment of Clostridium difficile–Associated Diarrhea, Stratified by Disease Severity

URL: https://academic.oup.com/cid/article/45/3/302/358373

Journal and year of publication: Clinical Infectious Disease, 2007

Trial Design: Randomized controlled trial

Population: 172 patients
Key inclusion criteria:
– Diarrhea (defined as ⩾3 nonformed stools in 24 h)
– C. difficile toxin A demonstrated in the stool within 48 h after study entry OR pseudomembranous colitis found on endoscopic examination
Key exclusion criteria:
– Suspected or proven life-threatening intraabdominal complications (i.e. perforated viscus, bowel obstruction)

Intervention Studied: Oral Vancomycin + Placebo

Control: Oral Metronidazole + Placebo

Outcomes:
– Percentage of patients achieving clinical cure:
– Patients with mild CDAD: Metronidazole: 90% vs Vancomycin: 98% (P = 0.36)
– Patients with severe CDAD: Metronidazole: 76% vs Vancomycin: 97% (P = 0.02)

The authors concluded that “Our findings suggest that metronidazole and vancomycin are equally effective for the treatment of mild CDAD, but vancomycin is superior for treating patients with severe CDAD.“

Citation: _{Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007 Aug 1;45(3):302-7. doi: 10.1086/519265. Epub 2007 Jun 19. PMID: 17599306.}

Hepatobiliary and Pancreatic disorders

ION-1 trial: Ledipasvir and sofosbuvir for HCV

Article Name: Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection

URL: https://www.nejm.org/doi/full/10.1056/nejmoa1402454

Journal and year of publication: NEJM, 2014

Trial Design: Randomized controlled trial

Population: 865 patients
Key inclusion criteria:
– Previously untreated patients with chronic HCV genotype 1 infection
– HCV RNA ≥ 10,000 IU/mL at Screening
Key exclusion criteria:
– Chronic liver disease of a non-HCV etiology
– Infection with HBV or HIV

Intervention Studied:
1) Ledipasvir and sofosbuvir for 12 weeks
2) Ledipasvir–sofosbuvir plus ribavirin for 12 weeks
3) Ledipasvir–sofosbuvir for 24 weeks
4) Ledipasvir–sofosbuvir plus ribavirin for 24 weeks

Control: See above

Outcomes:
– Percentage of patients meeting the criterion for a sustained virologic response:
– 12 weeks of (ledipasvir + sofosbuvir): 99% (95% CI:96 to 100)
– 12 weeks of (ledipasvir + sofosbuvir + ribavirin): 97% (95% CI:94 to 99)
– 24 weeks of (ledipasvir + sofosbuvir): 98% (95% CI:95 to 99)
– 24 weeks of (ledipasvir + sofosbuvir + ribavirin): 99% (95% CI:97 to 100)

The authors concluded that “Once-daily ledipasvir–sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection.“

Citation: _{Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, Romero-Gomez M, Zarski JP, Agarwal K, Buggisch P, Foster GR, Bräu N, Buti M, Jacobson IM, Subramanian GM, Ding X, Mo H, Yang JC, Pang PS, Symonds WT, McHutchison JG, Muir AJ, Mangia A, Marcellin P; ION-1 Investigators. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014 May 15;370(20):1889-98. doi: 10.1056/NEJMoa1402454. Epub 2014 Apr 11. PMID: 24725239.}

VALENCE trial: Sofosbuvir and Ribavirin for HCV 2 & 3

Article Name: Sofosbuvir and Ribavirin in HCV Genotypes 2 and 3

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1316145

Journal and year of publication: NEJM, 2014

Trial Design: Randomized controlled trial (Study was unblinded, study findings were redefined to be descriptive and not include hypothesis testing)

Population: 419 patients
Key inclusion criteria:
– Chronic infection with HCV genotype 2 or 3
– Serum HCV RNA levels of 10,000 IU per milliliter or higher
Key exclusion criteria:

Intervention Studied: Sofosbuvir–ribavirin

Control: Placebo (terminated later)

Outcomes:
– Percentage of patients meeting the criterion for a sustained virologic response:
– Patients with HCV genotype 2: 93% (95% CI: 85 to 98)
– Patients with HCV genotype 3: 85% (95% CI: 80 to 89)
– Response rates in subgroups: Those with cirrhosis: 68% vs those without: 91%

The authors concluded that “Therapy with sofosbuvir–ribavirin for 12 weeks in patients with HCV genotype 2 infection and for 24 weeks in patients with HCV genotype 3 infection resulted in high rates of sustained virologic response.“

Citation: _{Zeuzem S, Dusheiko GM, Salupere R, Mangia A, Flisiak R, Hyland RH, Illeperuma A, Svarovskaia E, Brainard DM, Symonds WT, Subramanian GM, McHutchison JG, Weiland O, Reesink HW, Ferenci P, Hézode C, Esteban R; VALENCE Investigators. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med. 2014 May 22;370(21):1993-2001. doi: 10.1056/NEJMoa1316145. Epub 2014 May 4. PMID: 24795201.}

Prednisolone for alcoholic hepatitis

Article Name: A Randomized Trial of Prednisolone in Patients with Severe Alcoholic Hepatitis

URL: https://www.nejm.org/doi/full/10.1056/NEJM199202203260802

Journal and year of publication: NEJM, 1992

Trial Design: Randomized controlled trial

Population: 419 patients
Key inclusion criteria:
– Biopsy-proved alcoholic hepatitis
– Spontaneous hepatic encephalopathy &/or discriminant-function value >32
Key exclusion criteria:
– Patients with gastrointestinal bleeding or bacterial infection

Intervention Studied: Prednisolone

Control: Placebo

Outcomes:
– Death (At day 66): Placebo: 16 out of 29 patients (mean survival, 45±8 percent) vs Prednisolone: 4 out of 32 patients (survival, 88±5 percent) (P = 0.001)

The authors concluded that “Treatment with prednisolone improves the short-term survival of patients with severe biopsy-proved alcoholic hepatitis.“

Citation: _{Ramond MJ, Poynard T, Rueff B, Mathurin P, Théodore C, Chaput JC, Benhamou JP. A randomized trial of prednisolone in patients with severe alcoholic hepatitis. N Engl J Med. 1992 Feb 20;326(8):507-12. doi: 10.1056/NEJM199202203260802. PMID: 1531090.}

Albumin for SBP

Article Name: Effect of Intravenous Albumin on Renal Impairment and Mortality in Patients with Cirrhosis and Spontaneous Bacterial Peritonitis

URL: https://www.nejm.org/doi/full/10.1056/NEJM199908053410603

Journal and year of publication: NEJM, 1999

Trial Design: Randomized clinical trial

Population: 126 patients
Key inclusion criteria:
– Polymorphonuclear-cell count in the ascitic fluid >250/ cubic millimeter
– Absence of findings suggestive of secondary peritonitis
– Serum creatinine not higher than 3 mg/dL
Key exclusion criteria:

Intervention Studied: Intravenous cefotaxime and intravenous albumin

Control: Intravenous cefotaxime alone

Outcomes:
– Percentage of patients developing renal impairment: Cefotaxime: 33% vs Cefotaxime + Albumin: 10% (P=0.002)
– In-hospital death: Cefotaxime: 29% vs Cefotaxime + Albumin: 10% (P=0.01)
– Mortality rate (at 3 months): Cefotaxime: 41% vs Cefotaxime + Albumin: 22%
(P=0.03)

The authors concluded that “In patients with cirrhosis and spontaneous bacterial peritonitis, treatment with intravenous albumin in addition to an antibiotic reduces the incidence of renal impairment and death in comparison with treatment with an antibiotic alone.“

Citation: _{Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz-del-Arbol L, Castells L, Vargas V, Soriano G, Guevara M, Ginès P, Rodés J. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med. 1999 Aug 5;341(6):403-9. doi: 10.1056/NEJM199908053410603. PMID: 10432325.}

Albumin for paracentesis

Article Name: Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis

URL: https://www.gastrojournal.org/article/0016-5085(88)90691-9/pdf

Journal and year of publication: Gastroenterology, 1988

Trial Design: Randomized clinical trial

Population: 105 patients
Key inclusion criteria:
– Cirrhosis with tense ascites
Key exclusion criteria:

Intervention Studied: Paracentesis + intravenous albumin infusion

Control: Paracentesis without albumin

Outcomes:
– Development of renal impairment or severe hyponatremia: Albumin group: 1 patient vs no albumin group: 11 patients (p<0.01)
– The no albumin group had significant elevation in BUN, plasma renin activity, aldosterone, and significant reduction in serum sodium concentration

The authors concluded that “These results indicate that intravenous albumin infusion is important in avoiding renal and electrolyte complications and activation of endogenous vasoactive systems in cirrhotics with ascites who are treated with repeated large-volume paracentesis. The development of such complications may impair survival in these patients.“

Citation: _{Ginès P, Titó L, Arroyo V, Planas R, Panés J, Viver J, Torres M, Humbert P, Rimola A, Llach J, et al. Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology. 1988 Jun;94(6):1493-502. doi: 10.1016/0016-5085(88)90691-9. PMID: 3360270.}

Beta-blockers for esophageal variceal bleeding prophylaxis

Article Name: Propranolol prevents first gastrointestinal bleeding in non-ascitic cirrhotic patients

URL: https://www.journal-of-hepatology.eu/article/0168-8278(89)90078-0/pdf

Journal and year of publication: Journal of Hepatology, 1989

Trial Design: Randomized clinical trial

Population: 174 patients
Key inclusion criteria:
– Patients with liver cirrhosis and large esophageal varices that never bled
Key exclusion criteria:
– Ascites were resistant to in-hospital diuretic treatment
– Chronic or recurrent encephalopathy
– Heart failure or obstructive lung disease

Intervention Studied: Propranolol

Control: Placebo

Outcomes:
– Patients free of bleeding (cumulative value over 42 months): Propranolol: 74% vs Placebo: 59% (No significant difference)
– For patients with no ascites at randomization: proportion of patients free of bleeding : Propranolol: 83% vs Placebo: 61% (P = 0.028)

The authors concluded that “Our conclusion was that propranolol prevents first bleeding in cirrhotic patients with large varices and without ascites. Further studies are needed to assess its effectiveness and safely in ascitic patients.“

Citation: _{Propranolol prevents first gastrointestinal bleeding in non-ascitic cirrhotic patients. Final report of a multicenter randomized trial. The Italian Multicenter Project for Propranolol in Prevention of Bleeding. J Hepatol. 1989 Jul;9(1):75-83. PMID: 2671121.}

Variceal ligation for esophageal variceal bleeding prophylaxis

Article Name: Endoscopic variceal ligation versus propranolol in prophylaxis of first variceal bleeding in patients with cirrhosis

URL: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1440-1746.2005.04071.x

Journal and year of publication: Journal of Gastroenterology and Hepatology, 2006

Trial Design: Randomized clinical trial

Population: 100 patients
Key inclusion criteria:
– Cirrhosis with esophageal varices at high risk of bleeding
– No previous bleeding from the upper GI trac
Key exclusion criteria:
– Gastric or ectopic varices

Intervention Studied: Endoscopic variceal ligation (EVL)

Control: Propranolol

Outcomes:
– Primary prophylaxis of variceal bleeding: EVL: 22% vs Propranolol: 24% (P=0.68)
– Overall mortality: EVL: 28% vs Propranolol: 24% (P=0.49)

The authors concluded that “Prophylaxis EVL is as effective and as safe as treatment with propranolol in decreasing the incidence of first variceal bleeding and death in cirrhotic patients with high-risk esophageal varices.“

Citation: _{Lay CS, Tsai YT, Lee FY, Lai YL, Yu CJ, Chen CB, Peng CY. Endoscopic variceal ligation versus propranolol in prophylaxis of first variceal bleeding in patients with cirrhosis. J Gastroenterol Hepatol. 2006 Feb;21(2):413-9. doi: 10.1111/j.1440-1746.2005.04071.x. PMID: 16509867.}

Lactulose for hepatic encephalopathy

Article Name: Secondary Prophylaxis of Hepatic Encephalopathy: An Open-Label Randomized Controlled Trial of Lactulose Versus Placebo

URL: https://www.gastrojournal.org/article/S0016-5085(09)00904-4/fulltext?referrer=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F

Journal and year of publication: Gastroenterology, 2009

Trial Design: Randomized clinical trial

Population: 140 patients
Key inclusion criteria:
– Cirrhotic patients recovered from encephalopathy admitted in study wards
Key exclusion criteria:
– Alcohol intake during the past 6 weeks.
– Hepatocellular carcinoma
– Previous TIPS or shunt surgery
– Nonhepatic metabolic encephalopathies

Intervention Studied: Lactulose

Control: Placebo

Outcomes:
– Percentage of patients developing HE during follow up (Median 14 months):
Lactulose group: 19.6% vs Placebo group: 46.8% (P =0.001)

The authors concluded that “Lactulose is effective for prevention of recurrence of HE in patients with cirrhosis.“

Citation: _{Sharma BC, Sharma P, Agrawal A, Sarin SK. Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo. Gastroenterology. 2009 Sep;137(3):885-91, 891.e1. doi: 10.1053/j.gastro.2009.05.056. Epub 2009 Jun 6. PMID: 19501587.}

MELD score study for cirrhosis

Article Name: MELD score and serum sodium in the prediction of survival of patients with cirrhosis awaiting liver transplantation

URL: https://gut.bmj.com/content/56/9/1283.long

Journal and year of publication: Gut, 2007

Trial Design: Retrospective cohort study

Population: 308 patients
Key inclusion criteria:
– Liver cirrhosis listed for transplantation
Key exclusion criteria:
– Hepatocellular carcinoma
– Retransplantation

Intervention Studied: N/a

Control: N/a

Outcomes:
– The only independent predictors of survival (at 3 and 12 months) were the MELD score and serum sodium

The authors concluded that “In patients with cirrhosis awaiting liver transplantation, serum sodium and MELD were found to be independent predictors of survival. Larger studies are needed to determine whether the addition of serum sodium to MELD can improve its prognostic accuracy.”

Citation: _{Londoño MC, Cárdenas A, Guevara M, Quintó L, de Las Heras D, Navasa M, Rimola A, Garcia-Valdecasas JC, Arroyo V, Ginès P. MELD score and serum sodium in the prediction of survival of patients with cirrhosis awaiting liver transplantation. Gut. 2007 Sep;56(9):1283-90. doi: 10.1136/gut.2006.102764. Epub 2007 Apr 23. PMID: 17452425; PMCID: PMC1954951.}

BISAP score study for pancreatitis

Article Name: A Prospective Evaluation of the Bedside Index for Severity in Acute Pancreatitis Score in Assessing Mortality and Intermediate Markers of Severity in Acute Pancreatitis

URL: Link

Journal and year of publication: The American Journal of Gastroenterology, 2009

Trial Design: Prospective cohort study

Population: 397 patients
Key inclusion criteria:
– Patients admitted with acute pancreatitis
Key exclusion criteria:

Intervention Studied: N/a

Control: N/a

Outcomes:
– Deaths: With an increase in BISAP score, there was a statistically significant increase in mortality (P< 0.0001)
– With a BISAP score of ≥3, there was an associated increased risk of organ failure and pancreatic necrosis

The authors concluded that “The BISAP score represents a simple way to identify patients at risk of increased mortality and the development of intermediate markers of severity within 24 h of presentation. This risk stratification capability can be utilized to improve clinical care and facilitate enrollment in clinical trials.“

Citation: _{Singh VK, Wu BU, Bollen TL, Repas K, Maurer R, Johannes RS, Mortele KJ, Conwell DL, Banks PA. A prospective evaluation of the bedside index for severity in acute pancreatitis score in assessing mortality and intermediate markers of severity in acute pancreatitis. Am J Gastroenterol. 2009 Apr;104(4):966-71. doi: 10.1038/ajg.2009.28. Epub 2009 Mar 17. PMID: 19293787.}

Enteral nutrition for pancreatitis

Article Name: Meta-analysis of parenteral nutrition versus enteral nutrition in patients with acute pancreatitis

URL: https://www.bmj.com/content/328/7453/1407.full

Journal and year of publication: BMJ, 2004

Trial Design: Meta-analysis of RCTs ( 6 trials)

Population: 263 patients
Key inclusion criteria:
– Trials that compared enteral nutrition with parenteral nutrition in patients with acute pancreatitis
Key exclusion criteria:

Intervention Studied: Enteral nutrition

Control: Parenteral nutrition

Outcomes:
– Enteral nutrition was associated with the following advantages:
– Lower incidence of infections: Relative risk: 0.45 (95% CI: 0.26 to 0.78), P = 0.004
– Reduced surgical interventions to control pancreatitis: Relative risk: 0.48 (95% CI: 0.22 to 1.0), P = 0.05
– Reduced hospital stay: Mean reduction: 2.9 days (95% CI: 1.6 days to 4.3 days),
P < 0.001
– There was no difference in mortality

The authors concluded that “Enteral nutrition should be the preferred route of nutritional support in patients with acute pancreatitis.“

Citation: _{Marik PE, Zaloga GP. Meta-analysis of parenteral nutrition versus enteral nutrition in patients with acute pancreatitis. BMJ. 2004 Jun 12;328(7453):1407. doi: 10.1136/bmj.38118.593900.55. Epub 2004 Jun 2. PMID: 15175229; PMCID: PMC421778.}

Do you think there are some important trials we should add to our site? Please contact us at landmarktrials@gmail.com with the trial name, link, and why you think it is a landmark paper!

Disclaimer: Please note that articles mentioned on this site are the property of their respective journals. The information from these articles was presented on this site under the Fair Use legal doctrine (Section 107 of the Copyright Act) as the data shared was limited in quantity, factual in nature, already published, and for the purpose of relaying and teaching socially beneficial medical knowledge. The work was attributed to the journals that published them with citations and links provided.

Gastroesophageal disorders

Intestinal disorders

Hepatobiliary and Pancreatic disorders

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