Week 42 – BeSt

“Clinical and Radiographic Outcomes of Four Different Treatment Strategies in Patients with Early Rheumatoid Arthritis (the BeSt Study).”

Arthritis & Rheumatism. 2005 Nov;52(11):3381-3390. [free full text]

Rheumatoid arthritis (RA) is among the most prevalent of the rheumatic diseases with a lifetime prevalence of 3.6% in women and 1.7% in men [1]. It is a chronic, systemic, inflammatory autoimmune disease of variable clinical course that can severely impact physical functional status and even mortality. Over the past 30 years, as the armamentarium of therapies for RA has exploded, there has been increased debate about the ideal initial therapy. The BeSt (Dutch: Behandel-Strategieën “treatment strategies”) trial was designed to compare, according to the authors, four of “the most frequently used and discussed strategies.” Regimens incorporating traditional disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, and newer therapies, such as TNF-alpha inhibitors, were compared directly.

The trial enrolled 508 DMARD-naïve patients with early rheumatoid arthritis. Pertinent exclusion criteria included history of cancer and pre-existing laboratory abnormalities or comorbidities (e.g. elevated creatinine or ALT, alcohol abuse, pregnancy or desire to conceive, etc.) that would preclude the use of various DMARDs. Patients were randomized to one of four treatment groups. Within each regimen, the Disease Activity Score in 44 joints (DAS-44) was assessed q3 months, and, if > 2.4, the medication regimen was uptitrated to the next step within the treatment group.

Four Treatment Groups

  1. Sequential monotherapy: methotrexate (MTX) 15mg/week, uptitrated PRN to 25-30mg/week. If insufficient control, the following sequence was pursued: sulfasalazine (SSZ) monotherapy, leflunomide monotherapy, MTX + infliximab, gold with methylprednisolone, MTX + cyclosporin A (CSA) + prednisone
  2. Step-up combination therapy: MTX 15mg/week, uptitrated PRN to 25-30mg/week. If insufficient control, SSZ was added, followed by hydroxychloroquine (HCQ), followed by prednisone. If patients failed to respond to those four drugs, they were switched to MTX + infliximab, then MTX + CSA + prednisone, and finally to leflunomide.
  3. Initial combination therapy with tapered high-dose prednisone: MTX 7.5 mg/week + SSZ 2000 mg/day + prednisone 60mg/day (tapered in 7 weeks to 7.5 mg/day). If insufficient control, MTX was uptitrated to 25-30 mg/week. Next, combination would be switched to MTX + CSA + prednisone, then MTX + infliximab, then leflunomide monotherapy, gold with methylprednisolone, and finally azathioprine with prednisone.
  4. Initial combination therapy with infliximab: MTX 25-30 mg/week + infliximab 3 mg/kg at weeks 0, 2, 6, and q8 weeks thereafter. There was a protocol for infliximab-dose uptitration starting at 3 months. If insufficient control on MTX and infliximab 10 mg/kg, patients were switched to SSZ, then leflunomide, then MTX + CSA + prednisone, then gold + methylprednisolone, and finally AZA with prednisone.

Once clinical response was adequate for at least 6 months, there was a protocol for tapering the drug regimen.

The primary endpoints were: 1) functional ability per the Dutch version of the Health Assessment Questionnaire (D-HAQ), collected by a blinded research nurse q3 months and 2) radiographic joint damage per the modified Sharp/Van der Heijde score (SHS). Pertinent secondary outcomes included DAS-44 score and laboratory evidence of treatment toxicity.

At randomization, enrolled RA patients had a median duration of symptoms of 23 weeks and median duration since diagnosis of RA of 2 weeks. Mean DAS-44 was 4.4 ± 0.9. 72% of patients had erosive disease. Mean D-HAQ score at 3 months was 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 (p < 0.001 for groups 1 and 2 vs. groups 3 and 4; paired tests otherwise insignificant). Mean D-HAQ at 1 year was 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 (p = 0.010 for group 1 vs. group 3, p = 0.003 for group 1 vs. group 4; paired tests otherwise insignificant). At 1 year, patients in group 3 or 4 had less radiographic progression in joint damage per SHS than patients in group 1 or 2. Median increases in SHS were 2.0, 2.5., 1.0, and 0.5 in groups 1-4, respectively (p = 0.003 for group 1 vs. group 3, p < 0.001 for group 1 versus group 4, p = 0.007 for group 2 vs. group 3, p < 0.001 for group 2 vs. group 4). Regarding DAS-44 score: low disease activity (DAS-44 ≤ 2.4) at 1 year was reached in 53%, 64%, 71%, 74% of groups 1-4, respectively (p = 0.004 for group 1 vs. group 3, p = 0.001 for group 1 vs. group 4, p not significant for other comparisons). There were no group differences in prevalence of adverse effects.

Overall, among patients with early RA, initial combination therapy that included either prednisone (group 3) or infliximab (group 4) resulted in better functional and radiographic improvement than did initial therapy with sequential monotherapy (group 1) or step-up combination therapy (group 2). In the discussion, the authors note that given the treatment group differences in radiographic progression of disease, “starting therapy with a single DMARD would be a missed opportunity in a considerable number of patients.” Contemporary commentary by Weisman notes that “the authors describe both an argument and a counterargument arising from their observations: aggressive treatment with combinations of expensive drugs would ‘overtreat’ a large proportion of patients, yet early suppression of disease activity may have an important influence on subsequent long‐term disability and damage.”

Fourteen years later, it is a bit difficult to place the specific results of this trial in our current practice. Its trial design is absolutely byzantine and compares the 1-year experience of a variety of complex protocols that theoretically have substantial eventual potential overlap. Furthermore, it is difficult to assess if the relatively small group differences in symptom (D-HAQ) and radiographic (SHS) scales were truly clinically significant even if they were statistically significant. The American College of Rheumatology 2015 Guideline for the Treatment of Rheumatoid Arthritis synthesized the immense body of literature that came before and after the BeSt study and ultimately gave a variety of conditional statements about the “best practice” treatment of symptomatic early RA. (See Table 2 on page 8.) The recommendations emphasized DMARD monotherapy as the initial strategy but in the specific setting of a treat-to-target strategy. They also recommended escalation to combination DMARDs or biologics in patients with moderate or high disease activity despite DMARD monotherapy.

References / Additional Reading:
1. “The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases.” Arthritis Rheum. 2011 Mar;63(3):633-9. [https://www.ncbi.nlm.nih.gov/pubmed/21360492]
2. BeSt @ Wiki Journal Club
3. “Progress toward the cure of rheumatoid arthritis? The BeSt study.” Arthritis Rheum. 2005 Nov;52(11):3326-32.
4. “Review: treat to target in rheumatoid arthritis: fact, fiction, or hypothesis?” Arthritis Rheumatol. 2014 Apr;66(4):775-82. [https://www.ncbi.nlm.nih.gov/pubmed/24757129]
5. “2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis” Arthritis Rheumatol. 2016 Jan;68(1):1-26
6. RheumDAS calculator

Summary by Duncan F. Moore, MD

Image Credit: Braegel, CC BY 3.0, via Wikimedia Commons

Week 41 – Transfusion Strategies for Upper GI Bleeding

“Transfusion Strategies for Acute Upper Gastrointestinal Bleeding”

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

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

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

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

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

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

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

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

 

Outcome:
Primary outcome: 45-day mortality

Secondary outcomes, selected:

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

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

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

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

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

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

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

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

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

Summary by Gordon Pelegrin, MD

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

Week 40 – PROSEVA

Prone Positioning in Severe Acute Respiratory Distress Syndrome
by the PROSEVA Study Group

N Engl J Med. 2013 June 6; 368(23):2159-2168 [free full text]

Prone positioning had been used for many years in ICU patients with ARDS in order to improve oxygenation. Per Dr. Sonti’s Georgetown Critical Care Top 40, the physiologic basis for benefit with proning lies in the idea that atelectatic regions of lung typically occur in the most dependent portion of an ARDS patient, with hyperinflation affecting the remaining lung. Periodic reversal of these regions via moving the patient from supine to prone and vice versa ensures no one region of the lung will have extended exposure to either atelectasis or overdistention. Although the oxygenation benefits have been long noted, the PROSEVA trial established mortality benefit.

Study patients were selected from 26 ICUs in France and 1 in Spain which had daily practice with prone positioning for at least 5 years. Inclusion criteria: ARDS patients intubated and ventilated <36hr with severe ARDS (defined as PaO2:FiO2 ratio <150, PEEP>5, and TV of about 6ml/kg of predicted body weight). (NB: by the Berlin definition for ARDS, severe ARDS is defined as PaO2:FiO2 ratio <100.) Patients were either randomized to the intervention of proning within 36 hours of mechanical ventilation for at least 16 consecutive hours (N=237) or to the control of being left in a semirecumbent (supine) position (N=229). The primary outcome was mortality at day 28. Secondary outcomes included mortality at day 90, rate of successful extubation (no reintubation or use of noninvasive ventilation x48hr), time to successful extubation, length of stay in the ICU, complications, use of noninvasive ventilation, tracheotomy rate, number of days free from organ dysfunction, ventilator settings, measurements of ABG, and respiratory system mechanics during the first week after randomization.

At the time of randomization in the study, the majority of characteristics were similar between the two groups, although the authors noted differences in the SOFA score and the use of neuromuscular blockers and vasopressors. The supine group at baseline had a higher SOFA score indicating more severe organ failure, and also had higher rate of vasopressor usage. The prone group had a higher rate of usage of neuromuscular blockade. The primary outcome of 28 day mortality was significantly lower in the prone group than in the supine group, at 16.0% vs 32.8% (p < 0.001, NNT = 6.0). This mortality decrease was still statistically significant when adjusted for the SOFA score. Secondary outcomes were notable for a significantly higher rate of successful extubation in the prone group (hazard ratio 0.45; 95% CI 0.29-0.7, p < 0.001). Additionally, the PaO2:FiO2 ratio was significantly higher in the supine group, whereas the PEEP and FiO2 were significantly lower. The remainder of secondary outcomes were statistically similar.

PROSEVA showed a significant mortality benefit with early use of prone positioning in severe ARDS. This mortality benefit was considerably larger than that seen in past meta-analyses, which was likely due to this study selecting specifically for patients with severe disease as well as specifying longer prone-positioning sessions than employed in prior studies. Critics have noted the unexpected difference in baseline characteristics between the two arms of the study. While these critiques are reasonable, the authors mitigate at least some of these complaints by adjusting the mortality for the statistically significant differences. With such a radical mortality benefit it might be surprising that more patients are not proned at our institution. One reason is that relatively few of our patients have severe ARDS. Additionally, proning places a high demand on resources and requires a coordinated effort of multiple staff. All treatment centers in this study had specially-trained staff that had been performing proning on a daily basis for at least 5 years, and thus were very familiar with the process. With this in mind, we consider the use of proning in patients meeting criteria for severe ARDS.

References and further reading:
1. PROSEVA @ 2 Minute Medicine
2. PROSEVA @ Wiki Journal Club
3. PROSEVA @ Georgetown Critical Care Top 40, pages 8-9
4. Life in the Fastlane, Critical Care Compendium, “Prone Position and Mechanical Ventilation”
5. PulmCCM.org, “ICU Physiology in 1000 Words: The Hemodynamics of Prone”

Summary by Gordon Pelegrin, MD

Image Credit: by James Heilman, MD, CC BY-SA 3.0, via Wikimedia Commons