Week 6 – SOLVD

“Effect of Enalapril on Survival in Patients with Reduced Left Ventricular Ejection Fractions and Congestive Heart Failure”

by the Studies of Left Ventricular Dysfunction (SOLVD) Investigators

N Engl J Med. 1991 Aug 1;325(5):293-302. [free full text]

Heart failure with reduced ejection fraction (HFrEF) is a very common and highly morbid condition. We now know that blockade of the renin-angiotensin-aldosterone system (RAAS) with an ACEi or ARB is a cornerstone of modern HFrEF treatment. The 1991 SOLVD trial played an integral part in demonstrating the benefit of and broadening the indication for RAAS blockade in HFrEF.

The trial enrolled patients with HFrEF and LVEF ≤ 35% who were already on treatment (but not on an ACEi) and had Cr ≤ 2.0 and randomized them to treatment with enalapril BID (starting at 2.5mg and uptitrated as tolerated to 20mg BID) or treatment with placebo BID (again, starting at 2.5mg and uptitrated as tolerated to 20mg BID). Of note, there was a single-blind run-in period with enalapril in all patients, followed by a single-blind placebo run-in period. Finally, the patient was randomized to his/her actual study drug in a double-blind fashion. The primary outcomes were all-cause mortality and death from or hospitalization for CHF. Secondary outcomes included hospitalization for CHF, all-cause hospitalization, cardiovascular mortality, and CHF-related mortality.

2569 patients were randomized. Follow-up duration ranged from 22 to 55 months. 510 (39.7%) placebo patients died during follow-up compared to 452 (35.2%) enalapril patients (relative risk reduction of 16% per log-rank test, 95% CI 5-26%, p = 0.0036). See Figure 1 for the relevant Kaplan-Meier curves. 736 (57.3%) placebo patients died or were hospitalized for CHF during follow-up compared to 613 (47.7%) enalapril patients (relative risk reduction 26%, 95% CI 18-34, p < 0.0001). Hospitalizations for heart failure, all-cause hospitalizations, cardiovascular deaths, and deaths due to heart failure were all significantly reduced in the enalapril group. 320 placebo patients discontinued the study drug versus only 182 patients in the enalapril group. Enalapril patients were significantly more likely to report dizziness, fainting, and cough. There was no difference in the prevalence of angioedema.

Treatment of HFrEF with enalapril significantly reduced mortality and hospitalizations for heart failure. The authors note that for every 1000 study patients treated with enalapril, approximately 50 premature deaths and 350 heart failure hospitalizations were averted. The mortality benefit of enalapril appears to be immediate and increases for approximately 24 months. Per the authors, “reductions in deaths and rates of hospitalization from worsening heart failure may be related to improvements in ejection fraction and exercise capacity, to a decrease in signs and symptoms of congestion, and also to the known mechanism of action of the agent – i.e., a decrease in preload and afterload when the conversion of angiotensin I to angiotensin II is blocked.” Strengths of this study include its double-blind, randomized design, large sample size, and long follow-up. The fact that the run-in period allowed for the exclusion prior to randomization of patients who did not immediately tolerate enalapril is a major limitation of this study.

Prior to SOLVD, studies of ACEi in HFrEF had focused on patients with severe symptoms. The 1987 CONSENSUS trial was limited to patients with NYHA class IV symptoms. SOLVD broadened the indication of ACEi treatment to a wider group of symptoms and correlating EFs. Per the current 2013 ACCF/AHA guidelines for the management of heart failure, ACEi/ARB therapy is a Class I recommendation in all patients with HFrEF in order to reduce morbidity and mortality.

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. Effects of enalapril on mortality in severe congestive heart failure – Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). 1987.
4. 2013 ACCF/AHA guideline for the management of heart failure: executive summary

Summary by Duncan F. Moore, MD

Week 5 – IDNT

“Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes”

aka the Irbesartan Diabetic Nephropathy Trial (IDNT)

N Engl J Med. 2001 Sep 20;345(12):851-60. [free full text]

Diabetes mellitus is the most common cause of ESRD in the US. In 1993, a landmark study in NEJM demonstrated that captopril (vs. placebo) slowed the deterioration in renal function in patients with T1DM. However, prior to this 2002 study, no study had addressed definitively whether a similar improvement in renal outcomes could be achieved with RAAS blockade in patients with T2DM. Irbesartan (Avapro) is an angiotensin II receptor blocker that was first approved in 1997 for the treatment of hypertension. Its marketer, Bristol-Meyers Squibb, sponsored this trial in hopes of broadening the market for its relatively new drug.

This trial randomized patients with T2DM, hypertension, and nephropathy (per proteinuria and elevated Cr) to treatment with either irbesartan, amlodipine, or placebo. The drug in each arm was titrated to achieve a target SBP ≤ 135, and all patients were allowed non-ACEi/non-ARB/non-CCB drugs as needed. The primary outcome was a composite of the doubling of serum Cr, onset of ESRD, or all-cause mortality. Secondary outcomes included individual components of the primary outcome and a composite cardiovascular outcome.

1715 patients were randomized. The mean blood pressure after the baseline visit was 140/77 in the irbesartan group, 141/77 in the amlodipine group, and 144/80 in the placebo group (p = 0.001 for pairwise comparisons of MAP between irbesartan or amlodipine and placebo). Regarding the primary composite renal endpoint, the unadjusted relative risk was 0.80 (95% CI 0.66-0.97, p = 0.02) for irbesartan vs. placebo, 1.04 (95% CI 0.86-1.25, p = 0.69) for amlodipine vs. placebo, and 0.77 (0.63-0.93, p = 0.006) for irbesartan vs. amlodipine. The groups also differed with respect to individual components of the primary outcome. The unadjusted relative risk of creatinine doubling was 33% lower among irbesartan patients than among placebo patients (p = 0.003) and was 37% lower than among amlodipine patients (p < 0.001). The relative risks of ESRD and all-cause mortality did not differ significantly among the groups. There were no significant group differences with respect to the composite cardiovascular outcome. Importantly, a sensitivity analysis was performed which demonstrated that the conclusions of the primary analysis were not impacted significantly by adjustment for mean arterial pressure achieved during follow-up.

In summary, irbesartan treatment in T2DM resulted in superior renal outcomes when compared to both placebo and amlodipine. This beneficial effect was independent of blood pressure lowering. This was a well-designed, double-blind, randomized, controlled trial. However, it was industry-sponsored, and in retrospect, its choice of study drug seems quaint. The direct conclusion of this trial is that irbesartan is renoprotective in T2DM. In the discussion of IDNT, the authors hypothesize that “the mechanism of renoprotection by agents that block the action of angiotensin II may be complex, involving hemodynamic factors that lower the intraglomerular pressure, the beneficial effects of diminished proteinuria, and decreased collagen formation that may be related to decreased stimulation of transforming growth factor beta by angiotensin II.” In September 2002, on the basis of this trial, the FDA broadened the official indication of irbesartan to include the treatment of type 2 diabetic nephropathy. This trial was published concurrently in NEJM with the RENAAL trial. RENAAL was a similar trial of losartan vs. placebo in T2DM and demonstrated a similar reduction in the doubling of serum creatinine as well as a 28% reduction in progression to ESRD. In conjunction with the original 1993 ACEi in T1DM study, these two 2002 ARB in T2DM studies led to the overall notion of a renoprotective class effect of ACEis/ARBs in diabetes. Enalapril and lisinopril’s patents expired in 2000 and 2002, respectively. Shortly afterward, generic, once-daily ACE inhibitors entered the US market. Ultimately, such drugs ended up commandeering much of the diabetic-nephropathy-in-T2DM market share for which irbesartan’s owners had hoped.

Further Reading/References:
1. “The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.” NEJM 1993.
2. CSG Captopril Trial @ Wiki Journal Club
3. IDNT @ Wiki Journal Club
4. IDNT @ 2 Minute Medicine
5. US Food and Drug Administration, New Drug Application #020757
6. RENAAL @ Wiki Journal Club
7. RENAAL @ 2 Minute Medicine

Summary by Duncan F. Moore, MD

Week 4 – Dexamethasone in Bacterial Meningitis

Streptococcus pneumoniae
Streptococcus pneumoniae

“Dexamethasone in Adults With Bacterial Meningitis”

N Engl J Med 2002; 347:1549-1556. [free full text]

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]

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]

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]

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]

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]

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]

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]

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