Duncan Moore – Page 9

Week 4 – Dexamethasone in Bacterial Meningitis

“Dexamethasone in Adults With Bacterial Meningitis”

N Engl J Med 2002; 347:1549-1556. [free full text]
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The current standard of care in the treatment of suspected bacterial meningitis in the developed world includes the administration of dexamethasone prior to or at the time of antibiotic initiation. The initial evaluation of this practice in part stemmed from animal studies, which demonstrated that dexamethasone reduced CSF concentrations of inflammatory markers as well as neurologic sequelae after meningitis. RCTs in the pediatric literature also demonstrated clinical benefit. The best prospective trial in adults was this 2002 study by de Gans et al.

The trial enrolled adults with suspected meningitis and randomized them to either dexamethasone 10mg IV q6hrs x4 days started 15-20 minutes before the first IV antibiotics or a placebo IV with the same administration schedule. The primary outcome was the Glasgow Outcome Scale at 8 weeks (1 = death, 2 = vegetative state, 3 = unable to live independently, 4 = unable to return to school/work, 5 = able to return to school/work). Secondary outcomes included death and focal neurologic abnormalities. Subgroup analyses were performed by organism.

301 patients were randomized. At 8 weeks, 15% of dexamethasone patients compared with 25% of placebo patients had an unfavorable outcome of Glasgow Outcome Scale score 1-4 (RR 0.59, 95% CI 0.37 – 0.94, p= 0.03). Among patients with pneumococcal meningitis, 26% of dexamethasone patients compared with 52% of placebo patients had an unfavorable outcome. There was no significant difference among treatment arms within the subgroup of patients infected with meningococcal meningitis. Overall, death occurred in 7% of dexamethasone patients and 15% of placebo patients (RR 0.48, 95% CI 0.24 – 0.96, p = 0.04). In pneumococcal meningitis, 14% of dexamethasone patients died, and 34% of placebo patients died. There was no difference in rates of focal neurologic abnormalities or hearing loss in either treatment arm (including within any subgroup).

In conclusion, early adjunctive dexamethasone improves mortality in bacterial meningitis. As noted in the above subgroup analysis, this benefit appears to be driven by the efficacy within the pneumococcal meningitis subgroup. Of note, the standard initial treatment regimen in this study was amoxicillin 2gm q4hrs for 7-10 days rather than our standard ceftriaxone + vancomycin +/- ampicillin. Largely on the basis of this study alone, the IDSA guidelines for the treatment of bacterial meningitis (2004) recommend dexamethasone 0.15 mg/kg q6hrs for 2-4 days with first dose administered 10-20 min before or concomitant with initiation of antibiotics. Dexamethasone should be continued only if CSF Gram stain, CSF culture, or blood cultures are consistent with pneumococcus.

References / Further Reading:
1. IDSA guidelines for management of bacterial meningitis (2004)
2. Wiki Journal Club
3. 2 Minute Medicine

Summary by Duncan F. Moore, MD

Photo Credit: CDC/Janice Carr. Content Providers(s): CDC/Dr. Richard Facklam. Public Health Image Library #262.

Week 3 – CHOIR

“Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease”

by the Investigators in the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR)

N Engl J Med. 2006 Nov 16;355(20):2085-98. [free full text]
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Anemia is a prevalent condition in CKD and ESRD. The anemia is largely attributable to the loss of erythropoietin production due to the destruction of kidney parenchyma. Thus erythropoiesis-stimulating agents (ESAs) were introduced to improve this condition. Retrospective data and small interventional trials suggested that treatment to higher hemoglobin goals (such as > 12 g/dL) was associated with improved cardiovascular outcomes. However, in 1998, a prospective trial in ESRD patients on HD with a hematocrit treatment target of 42% versus 30% demonstrated a trend toward increased rates of non-fatal MI and death in the higher-target group. In an effort to clarify the hemoglobin goal in CKD patients, the 2006 CHOIR trial was designed. It was hypothesized that treatment of anemia in CKD to a target of 13.5 g/dL would lead to fewer cardiac events and reduced mortality when compared to a target of 11.3 g/dL.

The trial enrolled adults with CKD (eGFR 15-50ml/min) and Hgb < 11.0 g/dL and notably excluded patients with active cancer. The patients were randomized to erythropoietin support regimens targeting a hemoglobin of either 13.5 g/dL or 11.3 g/dL. The primary outcome was a composite of death, MI, hospitalization for CHF, or stroke. Secondary outcomes included individual components of the primary outcome, need for renal replacement therapy, all-cause hospitalization, and various quality-of-life scores.

The study was terminated early due to an interim analysis revealing a < 5% chance that there would be a demonstrated benefit for the high-hemoglobin group by the scheduled end of the study. Results from 715 high-hemoglobin and 717 low-hemoglobin patients were analyzed. The mean change in hemoglobin was +2.5 g/dL in the high-hemoglobin group versus +1.2g/dL in the low-hemoglobin group (p<0.001). The primary endpoint occurred in 125 of the high-hemoglobin patients (17.5%) versus 97 of the low-hemoglobin patients (13.5%) [HR 1.34, 95% CI 1.03-1.74, p=0.03; number needed to harm = 25]. There were no significant group differences among the four components of the primary endpoint when analyzed as individual secondary outcomes, nor was there a difference in rates of renal replacement therapy. Any-cause hospitalization rates were 51.6% in the high-hemoglobin group versus 46.6% in the low-hemoglobin group (p=0.03). Regarding quality-of-life scores, both groups demonstrated similar, statistically significant improvements from their respective baseline values.

In patients with anemia and CKD, treatment to a higher hemoglobin goal of 13.5g/dL was associated with an increased incidence of a composite endpoint of death, MI, hospitalization for CHF, or stroke relative to a treatment goal of 11.3g/dL. There were no differences between the two groups in hospitalization rates or progression to renal replacement therapy, and the improvement in quality of life was similar among the two treatment groups. Thus this study demonstrated no additional benefit and some harm with the higher treatment goal. The authors noted that “this study did not provide a mechanistic explanation for the poorer outcome with the use of a high target hemoglobin level.” Limitations of this trial included its non-blinded nature and relatively high patient withdrawal rates. Following this trial, the KDOQI clinical practice guidelines for the management of anemia in CKD were updated to recommend a Hgb target of 11.0-12.0 g/dL. However, this guideline was superseded by the 2012 KDIGO guidelines which, on the basis of further evidence, ultimately recommend initiating ESA therapy only in iron-replete CKD patients with Hgb < 10 g/dL with the goal of maintaining Hgb between 10 and 11.5 g/dL. Treatment should be individualized in patients with concurrent malignancy.

Further Reading/References:
1. Besarab et al. “The Effects of Normal as Compared with Low Hematocrit Values in Patients with Cardiac Disease Who Are Receiving Hemodialysis and Epoetin.” N Engl J Med. 1998 Aug 27;339(9):584-90.
2. Wiki Journal Club
3. 2 Minute Medicine
4. National Kidney Foundation Releases Anemia Guidelines Update (2007) []
5. Pfeffer et al. “A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.” N Engl J Med. 2009;361(21):2019.
6. KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD

Summary by Duncan F. Moore, MD

Week 2 – Albumin in SBP

“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. [free full text]
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Renal failure commonly develops in the setting of SBP, and its development is a sensitive predictor of in-hospital mortality. The renal impairment is thought to stem from decreased effective arterial blood volume secondary to the systemic inflammatory response to the infection. In our current practice, there are certain circumstances in which we administer albumin early in the SBP disease course in order to reduce the risk of renal failure and mortality. Ultimately, our current protocol originated from the 1999 study of albumin in SBP by Sort et al.

The trial enrolled adults with SBP and randomized them to treatment with either cefotaxime and albumin infusion 1.5 gm/kg within 6hrs of enrollment, followed by 1 gm/kg on day 3 or cefotaxime alone. The primary outcome was the development of “renal impairment” (a “nonreversible” increase in BUN or Cr by more than 50% to a value greater than 30 mg/dL or 1.5 mg/dL, respectively) during hospitalization. The secondary outcome was in-hospital mortality.

126 patients were randomized. Both groups had similar baseline characteristics, and both had similar rates of resolution of infection. Renal impairment occurred in 10% of the albumin group and 33% of the cefotaxime-alone group (p=0.02). In-hospital mortality was 10% in the albumin group and 29% in the cefotaxime-alone group (p=0.01). 78% of patients that developed renal impairment died in-hospital, while only 3% of patients who did not develop renal impairment died. Plasma renin activity was significantly higher on days 3, 6, and 9 in the cefotaxime-alone group than in the albumin group, while there were no significant differences in MAP among the two groups at those time intervals. Multivariate analysis of all trial participants revealed that baseline serum bilirubin and creatinine were independent predictors of the development of renal impairment.

In conclusion, albumin administration reduces renal impairment and improves mortality in patients with SBP. The findings of this landmark trial were refined by a brief 2007 report by Sigal et al. entitled “Restricted use of albumin for spontaneous bacterial peritonitis.” “High-risk” patients, identified by baseline serum bilirubin of ≥ 4.0 mg/dL or Cr ≥ 1.0 mg/dL were given the intervention of albumin 1.5gm/kg on day 1 and 1gm/kg on day 3, and low-risk patients were not given albumin. None of the 15 low-risk patients developed renal impairment or died, whereas 12 of 21 (57%) of the high-risk group developed renal impairment, and 5 of the 21 (24%) died. The authors conclude that patients with bilirubin < 4.0 and Cr < 1.0 did not need scheduled albumin in the treatment of SBP. The current (2012) American Association for the Study of Liver Diseases guidelines for the management of adult patients with ascites due to cirrhosis do not definitively recommend criteria for albumin administration in SBP. Instead they summarize the aforementioned two studies. A 2013 meta-analysis of four reports/trials (including the two above) concluded that albumin infusion reduced renal impairment and improved mortality with pooled odds ratios approximately commensurate with those of the 1999 study by Sort et al. Ultimately, the current recommended practice per expert opinion is to perform albumin administration per the protocol outlined by Sigal et al. (2007).

References / Further Reading:
1. AASLD Guidelines for Management of Adult Patients with Ascites Due to Cirrhosis (skip to page 77)
2. Sigal et al. “Restricted use of albumin for spontaneous bacterial peritonitis.” Gut 2007.
3. Meta-analysis: “Albumin infusion improves outcomes of patients with spontaneous bacterial peritonitis: a meta-analysis of randomized trials”
4. Wiki Journal Club
5. 2 Minute Medicine

Summary by Duncan F. Moore, MD

Week 1 – CAST

“Mortality and Morbidity in Patients Receiving Encainide, Flecainide, or Placebo”

The Cardiac Arrhythmia Suppression Trial (CAST)

N Engl J Med. 1991 Mar 21;324(12):781-8. [free full text]
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Ventricular arrhythmias are common following MI, and studies have demonstrated that PVCs and other arrhythmias such as non-sustained ventricular tachycardia (NSVT) are independent risk factors for cardiac mortality following MI. As such, by the late 1980s, many patients with PVCs post-MI were treated with antiarrhythmic drugs in an attempt to reduce mortality. The 1991 CAST trial sought to prove what predecessor trials had failed to prove – that suppression of such rhythms post-MI would improve survival.

This trial took post-MI patients with PVCs (with no sustained VT) and reduced EF and randomized them to an open-label titration period in which encainide, flecainide, or moricizine was titrated to suppress at least 80% of the PVCs and 90% of the runs of NSVT. Patients were then either randomized to continuation of the antiarrhythmic drug assigned during the titration period or transitioned to a placebo. The primary outcome was death or cardiac arrest with resuscitation, “either of which was due to arrhythmia.”

The trial was terminated early due to increased mortality in the encainide and flecainide treatment groups. 1498 patients were randomized following successful titration during the open-label period, and they were reported in this paper. The results of the moricizine arm were reported later in a different paper (CAST-II). The RR of death or cardiac arrest due to arrhythmia was 2.64 (95% CI 1.60–4.36; number needed to harm = 28.2). See Figure 1 on page 783 for a striking Kaplan-Meier curve. The RR of death or cardiac arrest due to all causes was 2.38 (95% CI 1.59–3.57; NNH = 20.6). Regarding other secondary outcomes, cardiac death/arrest due to any cardiac cause was similarly elevated in the treatment group, and there were no significant differences in non-lethal endpoints among the treatment and placebo arms.

In this large RCT, the treatment of asymptomatic ventricular arrhythmias with encainide and flecainide in patients with LV dysfunction following MI resulted in increased mortality. This study provides a classic example of how a treatment that seems to make intuitive sense based on observational data can be easily and definitively disproven with a placebo-controlled trial with hard endpoints (e.g. death). Although PVCs and NSVT are associated with cardiac death post-MI and reducing these arrhythmias might seem like an intuitive strategy for reducing death, correlation does not equal causation. Modern expert opinion at UpToDate notes no role for suppression of asymptomatic PVCs or NSVT in the peri-infarct period. Indeed such suppression may increase mortality. As noted on Wiki Journal Club, modern ACC/AHA guidelines “do not comment on the use of antiarrhythmic medications in ACS care.”

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. CAST-I Trial @ ClinicalTrials.gov
4. CAST-II trial publication, NEJM 1992
5. UpToDate “Clinical features and treatment of ventricular arrhythmias during acute myocardial infarction”

Summary by Duncan F. Moore, MD

Image Credit: By CardioNetworks: Drj – CardioNetworks: Nsvt.png, CC BY-SA 3.0

Week 52 – EINSTEIN-PE

“Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism”

by the EINSTEIN-PE Investigators

N Engl J Med. 2012 Apr 5;366(14):1287-97. [free full text]
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Prior to the introduction of DOACs, the standard of care for treatment of acute VTE was treatment with a vitamin K antagonist (VKA, e.g. warfarin) bridged with LMWH. In 2010, the EINSTEIN-DVT study demonstrated the non-inferiority of rivaroxaban (Xarelto) versus VKA with an enoxaparin bridge in patients with acute DVT in the prevention of recurrent VTE. Subsequently, in this 2012 study, EINSTEIN-PE, the EINSTEIN investigators examined the potential role for rivaroxaban in the treatment of acute PE.

This open-label RCT compared treatment of acute PE (± DVT) with rivaroxaban (15mg PO BID x21 days, followed by 20mg PO daily) versus VKA with an enoxaparin 1mg/kg bridge until the INR was therapeutic for 2+ days and the patient had received at least 5 days of enoxaparin. Patients with cancer were not excluded if they had a life expectancy of ≥ 3 months, but they comprised only ~4.5% of the patient population. Treatment duration was determined by the discretion of the treating physician and was decided prior to randomization. Duration was also a stratifying factor in the randomization. The primary outcome was symptomatic recurrent VTE (fatal or nonfatal). The pre-specified noninferiority margin was 2.0 for the upper limit of the 95% confidence interval of the hazard ratio. The primary safety outcome was “clinically relevant bleeding.”

4833 patients were randomized. In the conventional-therapy group, the INR was in the therapeutic range 62.7% of the time. Symptomatic recurrent VTE occurred in 2.1% of patients in the rivaroxaban group and 1.8% of patients in the conventional-therapy group (HR 1.12, 95% CI 0.75–1.68, p = 0.003 for noninferiority). The p value for superiority of conventional therapy over rivaroxaban was 0.57. A first episode of “clinically relevant bleeding” occurred in 10.3% of the rivaroxaban group versus 11.4% of the conventional-therapy group (HR 0.90, 95% CI 0.76-1.07, p = 0.23).

In a large, open-label RCT, rivaroxaban was shown to be noninferior to standard therapy with a VKA + enoxaparin bridge in the treatment of acute PE. This was the first major RCT to demonstrate the safety and efficacy of a DOAC in the treatment of PE and led to FDA approval of rivaroxaban for the treatment of PE that same year. The following year, the AMPLIFY trial demonstrated that apixaban was noninferior to VKA + LMWH bridge in the prevention of recurrent VTE, and apixaban was also approved by the FDA for the treatment of PE. The 2016 Chest guidelines for Antithrombotic Therapy for VTE Disease recommend the DOACs rivaroxaban, apixaban, dabigatran, or edoxaban over VKA therapy in VTE not associated with cancer. In cancer-associated VTE, LMWH remains the recommended agent. (See the Week 25 – CLOT post.) As noted previously, a study earlier this year in NEJM demonstrated the noninferiority of edoxaban over LMWH in the treatment of cancer-associated VTE.

Further Reading/References:
1. EINSTEIN-DVT @ NEJM
2. EINSTEIN-PE @ Wiki Journal Club
3. EINSTEIN-PE @ 2 Minute Medicine
4. AMPLIFY @ Wiki Journal Club
5. “Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism” NEJM 2018

Summary by Duncan F. Moore, MD

Week 51 – Donor-Feces Infusion for Recurrent C. difficile

“Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile”

N Engl J Med. 2013 Jan 31;368(5):407-15. [free full text]
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Clostridium difficile infection (CDI) is a common, increasingly prevalent, and increasingly recurrent disease. As discussed in our 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

Week 50 – Sepsis-3

“The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)”

JAMA. 2016 Feb 23;315(8):801-10. [free full text]
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In practice, we recognize sepsis as a potentially life-threatening condition that arises secondary to infection. Because the SIRS criteria were of limited sensitivity and specificity in identifying sepsis and because our understanding of the pathophysiology of sepsis had purportedly advanced significantly during the interval since the last sepsis definition, an international task force of 19 experts was convened to define and prognosticate sepsis more effectively. The resulting 2016 Sepsis-3 definition was the subject of immediate and sustained controversy.

In the words of Sepsis-3, sepsis simply “is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.” The paper further defines organ dysfunction in terms of a threshold change in the SOFA score by 2+ points. However, the authors state that “the SOFA score is not intended to be used as a tool for patient management but as a means to clinically characterize a septic patient.” The authors note that qSOFA, an easier tool introduced in this paper, can identify promptly at the bedside patients “with suspected infection who are likely to have a prolonged ICU stay or die in the hospital.” A positive screen on qSOFA is identified as 2+ of the following: AMS, SBP ≤ 100, or respiratory rate ≥ 22. At the time of this endorsement of qSOFA, the tool had not been validated prospectively. Finally, septic shock was defined as sepsis with persistent hypotension requiring vasopressors to maintain MAP ≥ 65 and with a serum lactate > 2 despite adequate volume resuscitation.

As noted contemporaneously in the excellent PulmCrit blog post “Top ten problems with the new sepsis definition,” Sepsis-3 was not endorsed by the American College of Chest Physicians, the IDSA, any emergency medicine society, or any hospital medicine society. On behalf of the American College of Chest Physicians, Dr. Simpson published a scathing rejection of Sepsis-3 in Chest in May 2016. He noted “there is still no known precise pathophysiological feature that defines sepsis.” He went on to state “it is not clear to us that readjusting the sepsis criteria to be more specific for mortality is an exercise that benefits patients,” and said “to abandon one system of recognizing sepsis [SIRS] because it is imperfect and not yet in universal use for another system that is used even less seems unwise without prospective validation of that new system’s utility.”

In fact, the later validation of qSOFA demonstrated that the SIRS criteria had superior sensitivity for predicting in-hospital mortality while qSOFA had higher specificity. See the following posts at PumCrit for further discussion: [https://emcrit.org/isepsis/isepsis-sepsis-3-0-much-nothing/] [https://emcrit.org/isepsis/isepsis-sepsis-3-0-flogging-dead-horse/].

At UpToDate, authors note that “data of the value of qSOFA is conflicting,” and because of this, “we believe that further studies that demonstrate improved clinically meaningful outcomes due to the use of qSOFA compared to clinical judgement are warranted before it can be routinely used to predict those at risk of death from sepsis.”

Additional Reading:
1. PulmCCM, “Simple qSOFA score predicts sepsis as well as anything else”
2. 2 Minute Medicine

Summary by Duncan F. Moore, MD

Week 49 – 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]
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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 extensively. 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.

Population: 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

Intervention / Comparison: patients were randomized to one of the following four groups for 28 days of treatment

prednisolone-matched placebo daily + pentoxifylline-matched placebo TID
prednisolone 40mg daily + pentoxifylline-matched placebo TID
prednisolone-matched placebo daily + pentoxifylline 400mg TID
prednisolone 40mg daily + pentoxifylline 400mg TID

Outcome:
Primary – 28-day mortality
Secondary – mortality or liver transplant at 90 days and at 1 year

Results:
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. Wiki Journal Club
2. 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

Week 47 – VA NEPHRON-D

“Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy”

by the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) Investigators

N Engl J Med. 2013 Nov 14;369(20):1892-903. [free full text]
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Inhibition of the renin-angiotensin-aldosterone system (RAAS) decreases the progression of proteinuric kidney disease, such as diabetic nephropathy. Prior studies have demonstrated that the greater the proteinuria is reduced by RAAS inhibition, the slower the further loss of GFR. Therefore, it had been hypothesized that combination RAAS inhibition with both an ACEi and an ARB in diabetic kidney disease would reduce the rate of renal decline and incidence of ESRD. The investigators of the VA NEPHRON-D trial hypothesized that “the benefit in slowing the progression of kidney disease would outweigh the risks of hyperkalemia and AKI associated with more intensive blockade of the RAAS.”

Population: US veterans with T2DM, eGFR 30.0-89.9 ml/min, and urinary albumin/Cr ratio ≥ 300

Notable exclusion criteria: nondiabetic kidney disease, K > 5.5, current treatment with sodium polystyrene sulfonate (Kayexalate)

Intervention: losartan 100mg PO daily and lisinopril 10mg, uptitrated q2 weeks to 20mg and then 40mg, respectively, as tolerated (meaning no hyperkalemia or Cr rise > 30%)

Comparison: losartan 100mg PO daily and placebo, uptitrated q2 weeks as tolerated

(Note: prior to randomization, there was a run-in period with uptitration to target dose of losartan to ensure hyperkalemia did not develop prior to initiating the study drug.)

Outcome:
Primary – time to first occurrence of composite endpoint of decline in eGFR (≥ 30 ml/min if baseline eGFR ≥60 ml/min, or relative decrease of ≥ 50% if baseline eGFR < 60 ml/min), ESRD, or death

Secondary, selected:

first occurrence of decline in eGFR or ESRD
ESRD
cardiovascular events (MI, stroke, or hospitalization for CHF)
all-cause mortality
hyperkalemia (> 6, or requiring ED visit/hospitalization/dialysis)
AKI

Results:
724 patients were randomized to each treatment arm. Baseline characteristics were similar among the two groups. The trial was stopped early after the data and safety monitoring committee found increased rates of serious adverse events, hyperkalemia, and AKI in the combination-therapy group. Median follow-up at time of study closure was 2.2 years.

132 patients in the combination-therapy group (18.2%) and 152 patients in the monotherapy group (21.0%) met the primary composite endpoint of decline in eGFR, ESRD, or death (p = 0.30).

Decline in eGFR or progression to ESRD occurred in 77 (10.6%) of the combination-therapy group and 101 (14.0%) of the monotherapy group (p = 0.10). There were also no significant group differences in the individual rates of ESRD, all-cause mortality, or MI/stroke/CHF.

AKI events occurred 190 times in 130 patients in the combination-therapy group (12.2 events per 100 person-years). In comparison, there were only 105 AKI events in 80 patients in the monotherapy group (6.7 events per 100 person-years) [HR 1.7, 95% CI 1.3-2.2, p < 0.001]. Hyperkalemia occurred in 72 (9.9%) of the combination-therapy patients versus 32 (4.4%) of the monotherapy patients (p < 0.001).

Implication/Discussion:
Among patients with T2DM, CKD, and proteinuria, combination therapy with an ARB and ACEi did not reduce the progression of kidney disease or mortality relative to an ARB alone; in fact, combination therapy increased the risks of AKI and hyperkalemia.

This was a well-designed, double-blind, randomized, controlled trial with definitive results. Its results align with those of its contemporary studies ONTARGET (2008, combination ARB and ACEi vs. monotherapy) and ALTITUDE (2012, ARB or ACEi plus the direct renin inhibitor aliskiren vs. ARB or ACEi monotherapy), which demonstrated no benefit and increased adverse event rates with combination therapy.

Although dual RAAS blockade reduces proteinuria in diabetic nephropathy greater than monotherapy, it is not recommended currently due to a lack of benefit and increased adverse events.

Further Reading/References:
1. VA NEPHRON-D @ Wiki Journal Club
2. ONTARGET @ Wiki Journal Club
3. ALTITUDE @ PubMed

Summary by Duncan F. Moore, MD

Week 45 – Look AHEAD

“Cardiovascular Effects of Intensive Lifestyle Intervention in Type 2 Diabetes”

by the Look AHEAD (Action for Health in Diabetes) Research Group

N Engl J Med. 2013 Jul 11;369(2):145-54. [free full text]
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NIH treatment guidelines recommend weight loss in patients with T2DM and overweight or obesity. Such weight loss is associated with improvements in glycemic control, hypertension, and quality of life. While retrospective cohort studies and a prospective trial of bariatric surgery in T2DM suggested that weight loss was associated with reduction in rates of cardiovascular events and mortality, no prospective trial has demonstrated such benefits from non-surgical weight loss. The Look AHEAD study was designed to determine if aggressive lifestyle intervention for weight loss in T2DM could provide benefits in hard cardiovascular outcomes.

Population: patients with T2DM, age 45-75, and BMI 25+ (27+ if on insulin), A1c < 11%, SBP < 160 mmHg, DBP < 100 mmHg, and the ability to complete a maximal exercise test

Intervention: an “intensive lifestyle intervention” with goal weight loss ≥ 7.0%, implemented via weekly group and individual counseling (decreasing in frequency over course of study). Specific recommended interventions: caloric restriction to 1200-1800 kcal/day, use of meal-replacement products, ≥ 175 min/wk of moderate-intensity exercise

Comparison: “diabetes support and education” comprised of three group meetings per year focused on diet, exercise, and social support (yearly meetings starting year 5)
Outcome:
Primary – composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for angina.

Of note, hospitalization for angina was not a pre-specified component of the primary outcome. It was added 2 years into the trial after event rates of the other cardiovascular components were lower than expected.

Secondary

composite of death from cardiovascular causes, nonfatal MI, nonfatal stroke (the original primary outcome)
composite of death (all-cause), nonfatal MI, nonfatal stroke, hospitalization for angina
composite of death (all-cause), nonfatal MI, stroke, hospitalization for angina, CABG, PCI, hospitalization for heart failure, or peripheral vascular disease

Results:
2570 patients were randomized to the intensive lifestyle intervention (ILI) group, and 2575 were randomized to the diabetes support and education (DSE) group. Baseline characteristics were similar in both groups. Mean BMI was 36.0, and 14% of patients had a history of cardiovascular disease.

At one year, mean weight loss from baseline was 8.6% in the ILI group and 0.7% in the DSE group (p < 0.001); however, weight loss at the end of the study was 6.0% in the ILI group and 3.5% in the DSE group (p < 0.001). The average group difference in A1c was 0.22% lower in the ILI group (p < 0.001) although A1c values were slightly higher than baseline in both groups at the end of the study (see Figure 1D for the time course).

The trial was terminated prematurely after interim analysis revealed that the likelihood of a significant positive primary result was approximately 1%. Median follow up was 9.6 years at the time of termination.

There was no group difference in rates of the primary composite cardiovascular endpoint. The endpoint occurred in 403 patients in the ILI group and 418 patients in the DSE group (1.83 and 1.92 events per 100 person-years, respectively; HR 0.95, 95% CI 0.83-1.09, p = 0.51).

There were no group differences in rates of the secondary composite outcomes.

Implication/Discussion:
Among patients with T2DM and overweight or obesity, an intensive lifestyle intervention for weight loss was not associated with improved cardiovascular outcomes, when compared to a control group-based diabetes support and education intervention.

Overall, this trial was a notable failure. Despite the trial’s adequate power and its authors shifting the goalposts at 2 years into the study, the intervention did not demonstrate “hard” cardiovascular benefits. Furthermore, generalizability of this study is limited by its exclusion of patients who could not complete a maximal-fitness test at baseline. With respect to diet, this trial did not address diet composition, only caloric restriction and increased physical activity.

The authors suggest that “a sustained weight loss of more than that achieved in the intervention group may be required to reduce the risk of cardiovascular disease,” and thus the trial failed to return a positive result.

Weight loss in patients with T2DM and overweight or obesity remains a Class A recommendation by the American Diabetes Association. The ADA also notes that weight loss may be achieved at 2 years with a “Mediterranean” diet. The 2013 PREDIMED study demonstrated that such a diet reduces the risk of ASCVD in high-risk patients.

Further Reading/References:
1. Look AHEAD @ Wiki Journal Club
2. American Diabetes Association. “Executive Summary: Standards of Medical Care in Diabetes – 2013.”
3. PREDIMED @ Wiki Journal Club

Summary by Duncan F. Moore, MD