Category: Gastroenterology

“Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile”

N Engl J Med. 2013 Jan 31;368(5):407-15. [free full text]
—

Clostridioides (formerly Clostridium) difficile infection (CDI) is a common, increasingly prevalent, and increasingly recurrent disease. As discussed in the 2017-2018 Academic Year Week 43 post, the IDSA/SHEA guidelines published March 2018 now list vancomycin PO as first line treatment for initial, non-severe CDI. These guidelines also list fecal microbiota transplantation (FMT) as an option for treatment of a second or subsequent recurrence of CDI. FMT received a rating of “Strong [recommendation] / Moderate [level of evidence]” for this indication thanks to this 2013 trial by van Nood et al. – the first prospective RCT to compare antibiotic therapy to FMT in recurrent CDI.

This single-academic-center (Netherlands), open-label, randomized controlled trial compared three regimens for the treatment of recurrent CDI. One treatment arm received vancomycin 500mg PO QID x4-5 days followed by bowel lavage and then infusion of donor feces through nasoduodenal tube, another treatment arm received a standard 14-day vancomycin 500mg PO QID regimen, and the final treatment arm received a standard 14-day vancomycin regimen with additional bowel lavage on day 4 or 5. The primary endpoint was cure without relapse by 10 weeks.

43 patients were randomized prior to the termination of the trial due to the markedly higher rates of recurrent CDI among patients who did not receive FMT. Regarding the primary outcome, 13 (81%) of the FMT group were cured after the first infusion (and remained so) at 10 weeks, whereas resolution of CDI occurred in only 4 (31%) of the vancomycin-alone group and in only 3 (23%) of the vancomycin + bowel lavage group (p < 0.001 for both pairwise comparisons vs. FMT).

In this randomized controlled trial, fecal microbiota transplantation was superior to both vancomycin and vancomycin plus bowel lavage in the cure of recurrent Clostridioides difficile infection. Although this trial was small, its effect was enormous. As mentioned above, FMT is now recommended by guidelines for the treatment of multiply-recurrent CDI. FMT has been the subject of numerous published and ongoing trials, including this notable 2017 study by Kao et al. that demonstrated noninferiority of FMT delivered via oral capsules versus “conventional” colonoscopic delivery.

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. 2017 Update to IDSA/SHEA Clinical Practice Guidelines for Clostridium difficile Infection
4. Kao et. al, “Effect of Oral Capsule- vs Colonoscopy-Delivered Fecal Microbiota Transplantation on Recurrent Clostridium difficile Infection.” JAMA. 2017;318(20):1985-1993.
5. IDSA, “Fecal Microbiota Transplantation”
6. Food and Drug Administration, “Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies”

Summary by Duncan F. Moore, MD

Image Credit: CDC/ Lois S. Wiggs (PHIL #6260), Public Domain, via Wikimedia Commons

“Transfusion Strategies for Acute Upper Gastrointestinal Bleeding”

N Engl J Med. 2013 Jan 3;368(1):11-21. [free full text]
—

A restrictive transfusion strategy of 7 gm/dL was established following the previously discussed 1999 TRICC trial. Notably, both TRICC and its derivative study TRISS excluded patients who had an active bleed. In 2013, Villanueva et al. performed a study to establish whether there was benefit to a restrictive transfusion strategy in patients with acute upper GI bleeding.

The study enrolled consecutive adults presenting to a single center in Spain with hematemesis (or bloody nasogastric aspirate), melena, or both. Notable exclusion criteria included: a clinical Rockall score* of 0 with a hemoglobin level higher than 12g/dL, massive exsanguinating bleeding, lower GIB, patient refusal of blood transfusion, ACS, stroke/TIA, transfusion within 90 days, recent trauma or surgery

*The Rockall score is a system to assess risk for further bleeding or death on a scale from 0-11. Higher scores (3-11) indicate higher risk. Of the 648 patients excluded, the most common reason for exclusion (n = 329) was low risk of bleeding.

Intervention: restrictive transfusion strategy (transfusion threshold Hgb = 7.0 gm/dL) [n = 444]

Comparison: liberal transfusion strategy (transfusion threshold Hgb = 9.0 gm/dL) [n = 445]

During randomization, patients were stratified by presence or absence of cirrhosis.

As part of the study design, all patients underwent emergent EGD within 6 hours and received relevant hemostatic intervention depending on the cause of bleeding.

Outcome:
Primary outcome: 45-day mortality

Secondary outcomes, selected:

• • • Incidence of further bleeding associated with hemodynamic instability or hemoglobin drop > 2 gm/dL in 6 hours
    • Incidence and number of RBC transfusions
    • Other products and fluids transfused
    • Hgb level at nadir, discharge, and 45 days

Subgroup analyses: Patients were stratified by presence of cirrhosis and corresponding Child-Pugh class, variceal bleeding, and peptic ulcer bleeding. An additional subgroup analysis was performed to evaluate changes in hepatic venous pressure gradient between the two strategies.

Results:
The primary outcome of 45-day mortality was lower in the restrictive strategy (5% vs. 9%; HR 0.55, 95% CI 0.33-0.92; p = 0.02; NNT = 24.8). In subgroup analysis, this finding remained consistent for patients who had Child-Pugh class A or B but was not statistically significant among patients who had Class C. Further stratification for variceal bleeding and peptic ulcer disease did not make a difference in mortality.

Secondary outcomes:
Rates of further bleeding events and RBC transfusion, as well as number of products transfused, were lower in the restrictive strategy. Subgroup analysis demonstrated that rates of re-bleeding were lower in Child-Pugh class A and B but not in C. As expected, the restrictive strategy also resulted in the lowest hemoglobin levels at 24 hours. Hemoglobin levels among patients in the restrictive strategy were lower at discharge but were not significantly different from the liberal strategy at 45 days. There was no group difference in amount of non-RBC blood products or colloid/crystalloid transfused. Patients in the restrictive strategy experienced fewer adverse events, particularly transfusion reactions such as transfusion-associated circulatory overload and cardiac complications. Patients in the liberal-transfusion group had significant post-transfusion increases in mean hepatic venous pressure gradient following transfusion. Such increases were not seen in the restrictive-strategy patients.

Implication/Discussion:
In patients with acute upper GI bleeds, a restrictive strategy with a transfusion threshold 7 gm/dL reduces 45-day mortality, the rate and frequency of transfusions, and the rate of adverse reactions, relative to a liberal strategy with a transfusion threshold of 9 gm/dL.

In their discussion, the authors hypothesize that the “harmful effects of transfusion may be related to an impairment of hemostasis. Transfusion may counteract the splanchnic vasoconstrictive response caused by hypovolemia, inducing an increase in splanchnic blood flow and pressure that may impair the formation of clots. Transfusion may also induce abnormalities in coagulation properties.”

Subgroup analysis suggests that the benefit of the restrictive strategy is less pronounced in patients with more severe hepatic dysfunction. These findings align with prior studies in transfusion thresholds for critically ill patients. However, the authors note that the results conflict with studies in other clinical circumstances, specifically in the pediatric ICU and in hip surgery for high-risk patients.

There are several limitations to this study. First, its exclusion criteria limit its generalizability. Excluding patients with massive exsanguination is understandable given lack of clinical equipoise; however, this choice allows too much discretion with respect to the definition of a massive bleed. (Note that those excluded due to exsanguination comprised only 39 of 648.) Lack of blinding was a second limitation. Potential bias was mitigated by well-defined transfusion protocols. Additionally, there a higher incidence of transfusion-protocol violations in the restrictive group, which probably biased results toward the null. Overall, deviations from the protocol occurred in fewer than 10% of cases.

Further Reading/References:
1. Transfusion Strategies for Acute Upper GI Bleeding @ Wiki Journal Club
2. 2 Minute Medicine
3. TRISS @ Wiki Journal Club

Summary by Gordon Pelegrin, MD

Image Credit: Jeremias, CC BY-SA 3.0, via Wikimedia Commons

“Prednisolone or Pentoxifylline for Alcohol Hepatitis”

aka the Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial

N Engl J Med. 2015 Apr 23;372(17):1619-28. [free full text]
—

Severe alcoholic hepatitis is associated with short-term mortality as high as 30%. Treatment of alcoholic hepatitis with corticosteroids has been extensively studied and debated. Prior to this 2010 study, an analysis of the five largest studies of glucocorticoid treatment in alcoholic hepatitis concluded that there was a significant mortality benefit at 28 days among patients with severe disease. Similarly, the nonselective phosphodiesterase inhibitor pentoxifylline has been evaluated in alcoholic hepatitis. One of four RCTs showed a significant benefit, but two meta-analyses have not concluded that there is any benefit. The authors of the 2010 STOPAH trial sought to evaluate both therapies compared to placebos in a 2-by-2 factorial design.

The trial enrolled adults with a clinical diagnosis of alcoholic hepatitis, average alcohol consumption > 80 gm/day in men or 60 gm/day in women, total bilirubin > 4.7mg/dL, and a Maddrey discriminant function ≥ 32. Patients were randomized to one of the following four groups for 28 days of treatment.

1. 1. 1. prednisolone-matched placebo daily + pentoxifylline-matched placebo TID
      2. prednisolone 40mg daily + pentoxifylline-matched placebo TID
      3. prednisolone-matched placebo daily + pentoxifylline 400mg TID
      4. prednisolone 40mg placebo daily + pentoxifylline 400mg TID

The primary outcome was 28-day mortality. The major secondary outcome was mortality or liver transplant at 90 days and at 1 year.

Regarding randomization of the 1103 patients, 276 were randomized to placebo-placebo, 277 to prednisolone-placebo, 276 to pentoxifylline-placebo, and 274 to prednisolone-pentoxifylline. The trial was stopped early due to “limitations on funding.” However, all enrolled patients completed at least 28 days of follow-up. 33 patients were unable to complete 90-day and 1-year follow-up due to termination of the trial.

At 28 days, 45 of 269 (17%) of placebo-placebo patients, 38 of 266 (14%) of prednisolone-placebo patients, 50 of 258 (19%) of pentoxifylline-placebo patients, and 35 of 260 (13%) of prednisolone-pentoxifylline patients had died. The odds ratio for 28-day mortality among patients treated with prednisolone was 0.72 (95% CI 0.52-1.01, p = 0.06), and the odds ratio for patients treated with pentoxifylline was 1.07 (95% CI 0.77-1.49, p = 0.69).

Similarly, neither treatment was found to influence 90-day or 1-year mortality or liver transplantation. (See Table 2.) Infection occurred in 13% of patients who received prednisolone versus 7% of patients who did not receive prednisolone.

Implication/Discussion:
In patients with severe alcoholic hepatitis, neither prednisolone nor pentoxifylline reduced morality risk at 28 days. Additionally, neither drug reduced the combined secondary endpoint of mortality or liver transplantation at 90 days or 1 year.

This was a well-designed, randomized, double-blind, double-placebo-controlled trial. A notable limitation was this trial’s reliance on the clinical diagnosis of alcohol hepatitis, rather than tissue diagnosis. This may have reduced the power of the trial with respect to detecting a treatment effect. Contemporary authors also noted that harm may have come to study patients due to a lack of tapering of prednisolone at the end of the 28 days of treatment.

A 2015 meta-analysis that included the STOPAH trial concluded that prednisolone treatment reduced 28-day mortality.

Despite the negative results of this specific trial, corticosteroid treatment has remained a mainstay of the treatment of severe alcoholic hepatitis.

The generally accepted practice, as summarized by UpToDate, is treatment with prednisolone 40mg PO daily for 28 days in patients with discriminant function ≥ 32. (Prednisolone is preferred over prednisone because prednisone requires conversion in the liver to its active form prednisolone, and such conversion can be impaired in liver dysfunction.) Therapy should be terminated early after 7 days if patients fail to show improvement (either by parameters such as bilirubin or discriminant function or by improvement in the Lille score).

Further Reading/References:
1. STOPAH @ Wiki Journal Club
2. STOPAH @ 2 Minute Medicine
3. UpToDate, “Management and prognosis of alcoholic hepatitis”
4. American College of Gastroenterology, “ACG Clinical Guideline: Alcoholic Liver Disease” (2018)
5. European Association for Study of the Liver (EASL), “EASL Clinical Practice Guidelines: Management of Alcoholic Liver Disease” (2012)

Summary by Duncan F. Moore, MD

Image Credit: University of Alabama at Birmingham Department of Pathology, CC BY-SA 2.5, via Wikimedia Commons

“Rifaximin Treatment in Hepatic Encephalopathy”

N Engl J Med. 2010 Mar25;362(12):1071-81. [free full text]
—

As we are well aware at Georgetown, hepatic encephalopathy (HE) is highly prevalent among patients with cirrhosis, and admissions for recurrent HE place a significant burden on the medical system. The authors of this study note that HE is thought to result from “the systemic accumulation of gut-derived neurotoxins, especially ammonia, in patients with impaired liver function and portosystemic shunting.” Lactulose is considered the standard of care for the prevention of HE. It is thought to decrease the absorption of ammonia in the gut lumen through its cathartic effects and by alteration of colonic pH. The minimally absorbable oral antibiotic rifaximin is thought to further reduce ammonia production through direct antibacterial effects within the gut lumen. Thus the authors of this pivotal 2010 study sought to determine the additive effect of daily rifaximin prophylaxis in the prevention of HE.

The study enrolled adults with cirrhosis and 2+ episodes of overt HE during the past 6 months and randomized them to treatment with either rifaximin 550mg PO BID x6 months or placebo 550mg PO BID x6 months. The primary outcome was time to first breakthrough episode of HE (West Haven Score of 2+ or West Haven Score 0 –> 1 with worsening asterixis). Secondary outcomes included time to first hospitalization involving HE and adverse events, including those “possibly related to infection.”

299 patients were randomized. 140 and 159 patients were assigned to rifaximin and placebo, respectively. Baseline characteristics were similar among the two groups. Lactulose use prior to and during the study was similar in both groups at approximately 91%. Breakthrough HE occurred in 31 (22.1%) of the rifaximin patients and 73 (45.9%) of the placebo patients [HR 0.42, 95% CI 0.28-0.64, p < 0.001, absolute risk reduction 23.7%, NNT = 4.2]. This result was consistent within all tested subgroups, except patients with MELD score 19-24 and patients who were not using lactulose at baseline. (See Figure 3.) Hospitalization involving HE occurred in 19 (13.6%) of the rifaximin patients and 36 (22.6%) of the placebo patients [HR 0.50, 95% CI 0.29-0.87, p = 0.01, absolute risk reduction 9.1%, NNT = 11.0]. There were no differences in adverse events among the two treatment groups.

Thus, prophylactic rifaximin reduced the incidence of recurrent HE and its resultant hospitalizations. This landmark trial showed a clear treatment benefit with implied savings in healthcare utilization costs associated with HE recurrences and hospitalizations. This marked effect was demonstrated even in the setting of relatively good (91%) lactulose adherence in both treatment arms prior to and throughout the trial.  On the day this trial was published in 2010, the FDA approved rifaximin for “reduction in risk of overt hepatic encephalopathy recurrence” in adults.

Because rifaximin is not generic and remains quite expensive, its financial utility is limited from an insurance company’s perspective. There is no other comparable nonabsorbable antibiotic for this indication. UpToDate suggests starting with lactulose therapy and then adding a nonabsorbable antibiotic, such as rifaximin, both for the treatment of overt HE and for the prevention of recurrent HE. In practice, most insurance companies will require a prior authorization for outpatient rifaximin treatment, but in my recent experience, this process has been perfunctory and easy.

Further Reading/References:
1. ClinicalTrials.gov, NCT00298038
2. FDA, NDA approval letter for Xifaxan (rifaximin)
3. UpToDate, “Hepatic encephalopathy in adults: Treatment”

Summary by Duncan F. Moore, MD

Image Credit: Centers for Disease Control and Prevention / Dr. Edwin P. Ewing, Jr., US Public Domain, via Wikimedia Commons

“Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile”

N Engl J Med. 2013 Jan 31;368(5):407-15. [free full text]
—

Clostridioides (formerly Clostridium) difficile infection (CDI) is a common, increasingly prevalent, and increasingly recurrent disease. As discussed in the 2017-2018 Academic Year Week 43 post, the IDSA/SHEA guidelines published March 2018 now list vancomycin PO as first line treatment for initial, non-severe CDI. These guidelines also list fecal microbiota transplantation (FMT) as an option for treatment of a second or subsequent recurrence of CDI. FMT received a rating of “Strong [recommendation] / Moderate [level of evidence]” for this indication thanks to this 2013 trial by van Nood et al. – the first prospective RCT to compare antibiotic therapy to FMT in recurrent CDI.

This single-academic-center (Netherlands), open-label, randomized controlled trial compared three regimens for the treatment of recurrent CDI. One treatment arm received vancomycin 500mg PO QID x4-5 days followed by bowel lavage and then infusion of donor feces through nasoduodenal tube, another treatment arm received a standard 14-day vancomycin 500mg PO QID regimen, and the final treatment arm received a standard 14-day vancomycin regimen with additional bowel lavage on day 4 or 5. The primary endpoint was cure without relapse by 10 weeks.

43 patients were randomized prior to the termination of the trial due to the markedly higher rates of recurrent CDI among patients who did not receive FMT. Regarding the primary outcome, 13 (81%) of the FMT group were cured after the first infusion (and remained so) at 10 weeks, whereas resolution of CDI occurred in only 4 (31%) of the vancomycin-alone group and in only 3 (23%) of the vancomycin + bowel lavage group (p < 0.001 for both pairwise comparisons vs. FMT).

In this randomized controlled trial, fecal microbiota transplantation was superior to both vancomycin and vancomycin plus bowel lavage in the cure of recurrent Clostridium difficile infection. Although this trial was small, its effect was enormous. As mentioned above, FMT is now recommended by guidelines for the treatment of multiply-recurrent CDI. FMT has been the subject of numerous published and ongoing trials, including this notable 2017 study by Kao et al. that demonstrated noninferiority of FMT delivered via oral capsules versus “conventional” colonoscopic delivery.

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. 2017 Update to IDSA/SHEA Clinical Practice Guidelines for Clostridium difficile Infection
4. Kao et. al, “Effect of Oral Capsule- vs Colonoscopy-Delivered Fecal Microbiota Transplantation on Recurrent Clostridium difficile Infection.” JAMA. 2017;318(20):1985-1993.
5. IDSA, “Fecal Microbiota Transplantation”
6. Food and Drug Administration, “Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies”

Summary by Duncan F. Moore, MD

Image Credit: CDC/ Lois S. Wiggs (PHIL #6260), Public Domain, via Wikimedia Commons

“Rifaximin Treatment in Hepatic Encephalopathy”

N Engl J Med. 2010 Mar25;362(12):1071-81. [free full text]
—

As we are well aware at Georgetown, hepatic encephalopathy (HE) is highly prevalent among patients with cirrhosis, and admissions for recurrent HE place a significant burden on the medical system. The authors of this study note that HE is thought to result from “the systemic accumulation of gut-derived neurotoxins, especially ammonia, in patients with impaired liver function and portosystemic shunting.” Lactulose is considered the standard of care for the prevention of HE. It is thought to decrease the absorption of ammonia in the gut lumen through its cathartic effects and by alteration of colonic pH. The minimally absorbable oral antibiotic rifaximin is thought to further reduce ammonia production through direct antibacterial effects within the gut lumen. Thus the authors of this pivotal 2010 study sought to determine the additive effect of daily rifaximin prophylaxis in the prevention of HE.

The study enrolled adults with cirrhosis and 2+ episodes of overt HE during the past 6 months and randomized them to treatment with either rifaximin 550mg PO BID x6 months or placebo 550mg PO BID x6 months. The primary outcome was time to first breakthrough episode of HE (West Haven Score of 2+ or West Haven Score 0 –> 1 with worsening asterixis). Secondary outcomes included time to first hospitalization involving HE and adverse events, including those “possibly related to infection.”

299 patients were randomized. 140 and 159 patients were assigned to rifaximin and placebo, respectively. Baseline characteristics were similar among the two groups. Lactulose use prior to and during the study was similar in both groups at approximately 91%. Breakthrough HE occurred in 31 (22.1%) of the rifaximin patients and 73 (45.9%) of the placebo patients [HR 0.42, 95% CI 0.28-0.64, p<0.001, absolute risk reduction 23.7%, NNT = 4.2]. This result was consistent within all tested subgroups, except patients with MELD score 19-24 and patients who were not using lactulose at baseline. (See Figure 3.) Hospitalization involving HE occurred in 19 (13.6%) of the rifaximin patients and 36 (22.6%) of the placebo patients [HR 0.50, 95% CI 0.29-0.87, p = 0.01, absolute risk reduction 9.1%, NNT = 11.0]. There were no differences in adverse events among the two treatment groups.

Thus, prophylactic rifaximin reduced the incidence of recurrent HE and its resultant hospitalizations. This landmark trial showed a clear treatment benefit with implied savings in healthcare utilization costs associated with HE recurrences and hospitalizations. This marked effect was demonstrated even in the setting of relatively good (91%) lactulose adherence in both treatment arms prior to and throughout the trial.  On the day this trial was published in 2010, the FDA approved rifaximin for “reduction in risk of overt hepatic encephalopathy recurrence” in adults.

Because rifaximin is not generic and remains quite expensive, its financial utility is limited from an insurance company’s perspective. There is no other comparable nonabsorbable antibiotic for this indication. UpToDate suggests starting with lactulose therapy and then adding a nonabsorbable antibiotic, such as rifaximin, both for the treatment of overt HE and for the prevention of recurrent HE. In practice, most insurance companies will require a prior authorization for outpatient rifaximin treatment, but in my recent experience, this process has been perfunctory and easy.

Further Reading/References:
1. ClinicalTrials.gov, NCT00298038
2. FDA, NDA approval letter for Xifaxan (rifaximin)
3. UpToDate, “Hepatic encephalopathy in adults: Treatment”

Summary by Duncan F. Moore, MD

“Prednisolone or Pentoxifylline for Alcohol Hepatitis”

aka the Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial

N Engl J Med. 2015 Apr 23;372(17):1619-28. [free full text]
—

Severe alcoholic hepatitis is associated with short-term mortality as high as 30%. Treatment of alcoholic hepatitis with corticosteroids has been extensively studied and debated. Prior to this 2010 study, an analysis of the five largest studies of glucocorticoid treatment in alcoholic hepatitis concluded that there was a significant mortality benefit at 28 days among patients with severe disease. Similarly, the nonselective phosphodiesterase inhibitor pentoxifylline has been evaluated in alcoholic hepatitis. One of four RCTs showed a significant benefit, but two meta-analyses have not concluded that there is any benefit. The authors of the 2010 STOPAH trial sought to evaluate both therapies compared to placebos in a 2-by-2 factorial design.

The trial enrolled adults with a clinical diagnosis of alcoholic hepatitis, average alcohol consumption > 80 gm/day in men or 60 gm/day in women, total bilirubin > 4.7mg/dL, and a Maddrey discriminant function ≥ 32 [https://www.mdcalc.com/maddreys-discriminant-function-alcoholic-hepatitis]. Patients were randomized to one of the following four groups for 28 days of treatment.

1. 1. 1. prednisolone-matched placebo daily + pentoxifylline-matched placebo TID
      2. prednisolone 40mg daily + pentoxifylline-matched placebo TID
      3. prednisolone-matched placebo daily + pentoxifylline 400mg TID
      4. prednisolone 40mg placebo daily + pentoxifylline 400mg TID

The primary outcome was 28-day mortality. The major secondary outcome was mortality or liver transplant at 90 days and at 1 year.

Regarding randomization of the 1103 patients, 276 were randomized to placebo-placebo, 277 to prednisolone-placebo, 276 to pentoxifylline-placebo, and 274 to prednisolone-pentoxifylline. The trial was stopped early due to “limitations on funding.” However, all enrolled patients completed at least 28 days of follow-up. 33 patients were unable to complete 90-day and 1-year follow-up due to termination of the trial.

At 28 days, 45 of 269 (17%) of placebo-placebo patients, 38 of 266 (14%) of prednisolone-placebo patients, 50 of 258 (19%) of pentoxifylline-placebo patients, and 35 of 260 (13%) of prednisolone-pentoxifylline patients had died. The odds ratio for 28-day mortality among patients treated with prednisolone was 0.72 (95% CI 0.52-1.01, p = 0.06), and the odds ratio for patients treated with pentoxifylline was 1.07 (95% CI 0.77-1.49, p = 0.69).

Similarly, neither treatment was found to influence 90-day or 1-year mortality or liver transplantation. (See Table 2.) Infection occurred in 13% of patients who received prednisolone versus 7% of patients who did not receive prednisolone.

Implication/Discussion:
In patients with severe alcoholic hepatitis, neither prednisolone nor pentoxifylline reduced morality risk at 28 days. Additionally, neither drug reduced the combined secondary endpoint of mortality or liver transplantation at 90 days or 1 year.

This was a well-designed, randomized, double-blind, double-placebo-controlled trial. A notable limitation was this trial’s reliance on the clinical diagnosis of alcohol hepatitis, rather than tissue diagnosis. This may have reduced the power of the trial with respect to detecting a treatment effect. Contemporary authors also noted that harm may have come to study patients due to a lack of tapering of prednisolone at the end of the 28 days of treatment.

A 2015 meta-analysis that included the STOPAH trial concluded that prednisolone treatment reduced 28-day mortality.

Despite the negative results of this specific trial, corticosteroid treatment has remained a mainstay of the treatment of severe alcoholic hepatitis.

The generally accepted practice, as summarized by UpToDate, is treatment with prednisolone 40mg PO daily for 28 days in patients with discriminant function ≥ 32. (Prednisolone is preferred over prednisone because prednisone requires conversion in the liver to its active form prednisolone, and such conversion can be impaired in liver dysfunction.) Therapy should be terminated early after 7 days if patients fail to show improvement (either by parameters such as bilirubin or discriminant function or by improvement in the Lille score).

Further Reading/References:
1. STOPAH @ Wiki Journal Club
2. STOPAH @ 2 Minute Medicine
3. UpToDate, “Management and prognosis of alcoholic hepatitis”
4. American College of Gastroenterology, “ACG Clinical Guideline: Alcoholic Liver Disease” (2018)
5. European Association for Study of the Liver (EASL), “EASL Clinical Practice Guidelines: Management of Alcoholic Liver Disease” (2012)

Summary by Duncan F. Moore, MD

Image Credit: University of Alabama at Birmingham Department of Pathology, CC BY-SA 2.5, via Wikimedia Commons