Week 43 – STOPAH

“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. 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.

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

Week 42 – RAVE

“Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis”

by the Rituximab in ANCA-Associated Vasculitis-Immune Tolerance Network (RAVE-ITN) Research Group

N Engl J Med. 2010 Jul 15;363(3):221-32. [free full text]

ANCA-associated vasculitides, such as granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis) and microscopic polyangiitis (MPA) are often rapidly progressive and highly morbid. Mortality in untreated generalized GPA can be as high as 90% at 2 years. Since the early 1980s, cyclophosphamide (CYC) with corticosteroids has been the best treatment option for induction of disease remission in GPA and MPA. Unfortunately, the immediate and delayed adverse effect profile of CYC can be burdensome. The role of B lymphocytes in the pathogenesis of these diseases has been increasingly appreciated over the past 20 years, and this association inspired uncontrolled treatment studies with the anti-CD20 agent rituximab that demonstrated promising preliminary results. Thus the RAVE trial was performed to compare rituximab to cyclophosphamide, the standard of care.

Population:      ANCA-positive patients with “severe” GPA or MPA and a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS/WG) of 3+.

notable exclusion: patients intubated due to alveolar hemorrhage, patients with Cr > 4.0

Intervention:    rituximab 375mg/m2 IV weekly x4 + daily placebo-CYC + pulse-dose corticosteroids with oral maintenance and then taper

Comparison:   placebo-rituximab infusion weekly x4 + daily CYC + pulse-dose corticosteroids with oral maintenance and then taper


primary end point = clinical remission, defined as a BVAS/WG of 0 and successful completion of prednisone taper

primary outcome = noninferiority of rituximab relative to CYC in reaching 1º end point

authors specified non-inferiority margin as a -20 percentage point difference in remission rate

subgroup analyses (pre-specified) = type of ANCA-associated vasculitis, type of ANCA, “newly-diagnosed disease,” relapsing disease, alveolar hemorrhage, and severe renal disease

secondary outcomes = rate of disease flares, BVAS/WG of 0 during treatment with prednisone at a dose of less than 10mg/day, cumulative glucocorticoid dose, rates of adverse events, SF-36 scores

197 patients were randomized, and baseline characteristics were similar among the two groups (e.g. GPA vs. MPA, relapsed disease, etc.). 75% of patients had GPA. 64% of the patients in the rituximab group reached remission, while 53% of the control patients did. This 11 percentage point difference among the treatment groups was consistent with non-inferiority (p < 0.001). However, although more rituximab patients reached the primary endpoint, the difference between the two groups was statistically insignificant, and thus superiority of rituximab could not be established (95% CI -3.2 – 24.3 percentage points difference, p = 0.09). Subgroup analysis was notable only for superiority of rituximab in relapsed patients (67% remission rate vs. 42% in controls, p=0.01). Rates of adverse events and treatment discontinuation were similar among the two groups.

Rituximab + steroids is as effective as cyclophosphamide + steroids in inducing remission in severe GPA and MPA.

This study initiated a major paradigm shift in the standard of care of ANCA-associated vasculitis. The following year, the FDA approved rituximab + steroids as the first-ever treatment regimen approved for GPA and MPA.  It spurred numerous follow up trials, and to this day expert opinion is split over whether CYC or rituximab should be the initial immunosuppressive therapy in GPA/MPA with “organ-threatening or life-threatening disease.”

Non-inferiority trials are increasingly common, and careful attention needs to be paid to their methodology. Please read more in the following two articles: [http://www.nejm.org/doi/full/10.1056/NEJMra1510063] and [http://www.rds-sc.nihr.ac.uk/study-design/quantitative-studies/clinical-trials/non-inferiority-trials/]

Further Reading/References:
1. “Wegener granulomatosis: an analysis of 158 patients” (1992)
2. RAVE @ ClinicalTrials.gov
3. “Challenges in the Design and Interpretation of Noninferiority Trials,” NEJM (2017)
4. “Clinical Trials – Non-inferiority Trials”
5. RAVE @ Wiki Journal Club
6. RAVE @ 2 Minute Medicine

Summary by Duncan F. Moore, MD

Week 41 – HAS-BLED


“A Novel User-Friendly Score (HAS-BLED) To Assess 1-Year Risk of Major Bleeding in Patients with Atrial Fibrillation”

Chest. 2010 Nov;138(5):1093-100. [free full text]

Atrial fibrillation (AF) is a well-known risk factor for ischemic stroke. Stroke risk is further increased by individual comorbidities, such as CHF, HTN, and DM, and can be stratified with scores, such as CHADS2 and CHA2DS2VASC. Patients with intermediate stroke risk are recommended to be treated with oral anticoagulation (OAC). However, stroke risk is often also closely related to bleeding risk, and the benefits of anticoagulation for stroke need to be weighed against the added risk of bleeding. At the time of this study, there were no validated and user-friendly bleeding risk-stratification schemes. This study aimed to develop a practical risk score to estimate the 1-year risk of major bleeding (as defined in the study) in a contemporary, real world cohort of patients with AF.

The study enrolled adults with an EKG or Holter-proven diagnosis of AF. (Patients with mitral valve stenosis or previous valvular surgery were excluded.) No experiment was performed in this retrospective cohort study.

In a derivation cohort, the authors retrospectively performed univariate analyses to identify a range of clinical features associated with major bleeding (p < 0.10). Based on systematic reviews, they added additional risk factors for major bleeding. Ultimately, what resulted was a list of comprehensive risk factors deemed HAS-BLED:

H – Hypertension (> 160 mmHg systolic)

A – Abnormal renal (HD, transplant, Cr > 2.26 mg/dL) and liver function (cirrhosis, bilirubin > 2x normal w/ AST/ALT/ALP > 3x normal) – 1 pt each for abnormal renal or liver function

S – Stroke

B – Bleeding (prior major bleed or predisposition to bleed)

L – Labile INRs (time in therapeutic range < 60%)

E – Elderly (age > 65)

D – Drugs (i.e. ASA, clopidogrel, NSAIDs) or alcohol use (> 8 units per week) concomitantly – 1 pt each for use of either

Each risk factor was equivalent to one point. The HAS-BLED score was then compared to the HEMORR2HAGES scheme, a prior tool for estimating bleeding risk.


      • incidence of major bleeding within 1 year, overall
      • bleeds per 100 patient-years, by HAS-BLED score
      • c-statistic for the HAS-BLED score in predicting the risk of bleeding


      • major bleeding = bleeding causing hospitalization, Hgb drop >2 g/L, or requiring blood transfusion, that was not a hemorrhagic stroke
      • hemorrhagic stroke = focal neurologic deficit of sudden onset, diagnosed by a neurologist, lasting >24h and caused by bleeding

3,456 patients with AF without mitral valve stenosis or valve surgery who completed their 1-year follow-up were analyzed retrospectively. 64.8% (2242) of these patients were on OAC (12.8% of whom on concurrent antiplatelet therapy), 24% (828) were on antiplatelet therapy alone, and 10.2% (352) received no antithrombotic therapy. 1.5% (53) of patients experienced a major bleed during the first year, with 17% (9) of these patients sustaining intracerebral hemorrhage.

HAS-BLED Score       Bleeds per 100-patient years
0                                       1.13
1                                       1.02
2                                       1.88
3                                       3.74
4                                       8.70
5                                      12.50
6*                                    0.0                   *(n = 2 patients at risk, neither bled)

Patients were given a HAS-BLED score and a HEMORR2HAGES score. C-statistics were then used to determine the predictive accuracy of each model overall as well as within patient subgroups (OAC alone, OAC + antiplatelet, antiplatelet alone, no antithrombotic therapy).

C statistics for HAS-BLED were as follows: for overall cohort, 0.72 (95%CI 0.65-0.79); for OAC alone, 0.69 (95%CI 0.59-0.80); for OAC + antiplatelet, 0.78 (95%CI 0.65-0.91); for antiplatelet alone, 0.91 (95%CI 0.83-1.00); and for those on no antithrombotic therapy, 0.85 (95%CI 0.00-1.00).

C statistics for HEMORR2HAGES were as follows: for overall cohort, 0.66 (95%CI 0.57-0.74); for OAC alone, 0.64 (95%CI 0.53-0.75); for OAC + antiplatelet, 0.83 (95%CI 0.74-0.91); for antiplatelet alone, 0.83 (95%CI 0.68-0.98); and for those without antithrombotic therapy, 0.81 (95%CI 0.00-1.00).

This study helped to establish a practical and user-friendly assessment of bleeding risk in AF. HAS-BLED is superior to its predecessor HEMORR2HAGES in that it has an easier-to-remember acronym and is quicker and simpler to perform. All of its risk factors are readily available from the clinical history or are routinely tested. Both stratification tools had a broadly similar c-statistics for the overall cohort – 0.72 for HAS-BLED versus 0.66 for HEMORR2HAGES respectively. However, HAS-BLED was particularly useful when looking at antiplatelet therapy alone or no antithrombotic therapy at all (0.91 and 0.85, respectively).

This study is useful because it provides evidence-based, easily-calculable, and actionable risk stratification in assessing bleeding risk in AF. In prior studies, such as ACTIVE-A (ASA + clopidogrel versus ASA alone for patients with AF deemed unsuitable for OAC), almost half of all patients (n= ~3500) were given a classification of “unsuitable for OAC,” which was based solely on physician clinical judgement alone without a predefined objective scoring. Now, physicians have an objective way to assess bleed risk rather than “gut feeling” or wanting to avoid iatrogenic insult.

The RE-LY trial used the HAS-BLED score to decide which patients with AF should get the standard dabigatran dose (150mg BID) versus a lower dose (110mg BID) for anticoagulation. This risk-stratified dosing resulted in a significant reduction in major bleeding compared with warfarin and maintained a similar reduction in stroke risk.

Furthermore, the HAS-BLED score could allow the physician to be more confident when deciding which patients may be appropriate for referral for a left atrial appendage occlusion device (e.g. Watchman).

The study had a limited number of major bleeds and a short follow-up period, and thus it is possible that other important risk factors for bleeding were not identified. Also, there were large numbers of patients lost to 1-year follow-up. These patients were likely to have had more comorbidities and may have transferred to nursing homes or even have died – which may have led to an underestimate of bleeding rates. Furthermore, the study had a modest number of very elderly patients (i.e. 75-84 and ≥ 85), who are likely to represent the greatest bleeding risk.

Bottom Line:
HAS-BLED provides an easy, practical tool to assess the individual bleeding risk of patients with AF. Oral anticoagulation should be considered for scores of 3 or less. When HAS-BLED scores are ≥ 4, it is reasonable to think about alternatives to oral anticoagulation.

Further Reading/References:
1. HAS-BLED @ 2 Minute Medicine
2. ACTIVE-A trial
3. RE-LY trial
4. RE-LY @ Wiki Journal Club
5. HAS-BLED Calculator
6. HEMORR2HAGES Calculator
7. CHADS2 Calculator
8. CHA2DS2VASC Calculator
9. Watchman (for Healthcare Professionals)
10. “Bleeding Risk Scores in Atrial Fibrillation: Helpful or Harmful?” Journal of the American Heart Association (2018)

Summary by Patrick Miller, MD

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