“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:
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

Primary – 28-day mortality
Secondary – 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. 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 48 – 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. The recommendation for patients with intermediate stroke risk is treatment with oral anticoagulation (OAC). However, stroke risk is often 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.

Population: adults with EKG or Holter-proven diagnosis of AF
Exclusion criteria: mitral valve stenosis, valvular surgery

(Patients were identified from the prospectively developed database of the multi-center Euro Heart Survey on AF. Among 5,272 patients with AF, 3,456 were free of mitral valve stenosis or valve surgery and completed their 1-year follow-up assessment.)

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, the result was a list of comprehensive risk factors that make up the acronym 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 represents one point each. The HAS-BLED score was then compared to the HEMORR2HAGES scheme, a previously developed tool for estimating bleeding risk.


  • incidence of major bleeding within 1 year
  • bleeds per 100 patient-years, stratified 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 bleeding requiring blood transfusion (excluded hemorrhagic stroke)
  • hemorrhagic stroke: focal neurologic deficit of sudden onset that is diagnosed by a neurologist, lasting > 24h, and caused by bleeding

3,456 AF patients (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 (with 12.8% (286) of this subset 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. 17% (9) of these patients sustained 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, and no antithrombotic therapy).

C statistics for HAS-BLED:
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:
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 on no 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 because the acronym is easier to remember, the assessment is quicker and simpler to perform, and all risk factors are readily available from the clinical history or routine testing. Both stratification tools had (grossly) similar c-statistics for the overall cohort – 0.72 for HAS-BLED versus 0.66 for HEMORR2HAGES. 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 the assessment of 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 physicians’ clinical judgement 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) rather than a lower dose (110mg BID) for anticoagulation. This risk-stratified dosing resulted in a significant reduction in major bleeding compared with warfarin but 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 likely had more comorbidities and may have transferred to nursing homes or even died. Their loss to follow-up and thus exclusion from this retrospective study may have led to an underestimate of true bleeding rates. Furthermore, generalizability is limited by the modest number of very elderly patients (i.e. 75-84 and ≥85), who likely represent the greatest bleeding risk. Finally, this study did not specify what proportion of its patients were on warfarin for their OAC, but given that dabigatran, rivaroxaban, and apixaban were not yet approved for use in Europe (2008, 2008, and 2011, respectively) for the majority of the study, we can assume most patients were on warfarin. Thus the generalizability of HAS-BLED risk stratification to the DOACs is limited.

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. If HAS-BLED scores are ≥4, it is reasonable to think about alternatives to oral anticoagulation.

Further Reading/References:
1. 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. Watchman (for Healthcare Professionals)

Summary by Patrick Miller, MD