Category Archives: Mac’s High-Impact CCM article summaries

Ely et al. Efficacy and Safety of Baricitinib Plus Standard Care for the Treatment of Critically Ill Hospitalized Adults with COVID-19 on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation: An Exploratory, Randomized, Placebo-Controlled Trial. Lancet Respiratory Medicine 2022

Question: Does the use of the oral selective Janus kinase 1/2 inhibitor baricitinib improve mortality in patients with severe COVID-19 requiring invasive mechanical ventilation (IMV) or ECMO?

Why ask it: While several randomized controlled trials have studied the use of baricitinib in hospitalized patients with COVID-19, there is minimal data on the safety and efficacy of baricitinib when used in patients who require IMV or ECMO.

Intervention: 101 patients in 4 countries with COVID-19 and at least one elevated inflammatory marker (CRP, D-dimer, LDH, ferritin) requiring IMV or ECMO randomized to baricitinib 4mg daily or placebo for up to 14 days (baricitinib dose-reduced based on eGFR). All other aspects of care were left to the treating team.

Results (written as baricitinib vs placebo):

• All-cause mortality at day 28
  • 39% vs 58% (HR, 0.54 [95% CI, 0.31 – 0.96]), p=0.03
• All-cause mortality at day 60
  • 45% vs 62% (HR, 0.56 [95% CI, 0.33 – 0.97]), p=0.027
• No significant difference between study groups in ventilator free days, overall improvement based on NIAID-OS, and duration of hospitalization

Conclusion: In patients with severe COVID-19 requiring IMV or ECMO, the use of baricitinib was associated with a reduction in both 28-day and 60-day mortality.

Comment:

• This trial is an exploratory extension of the COV-BARRIER trial (Lancet Resp Med, 2021) a multinational, phase-3, randomized, placebo-controlled trial of baricitinib in ~1,500 hospitalized patients with COVID-19 not requiring IMV or ECMO. While there was no significant difference in the primary outcome (a composite endpoint of the proportion of patients who progressed to HFNC, NIV, IMV, or death by day 28), there was a significant reduction in a secondary endpoint of 28-day mortality (8% with baricitinib vs 13% with placebo (HR, 0.57 [95% CI, 0.41 – 0.78]).

• The other large trial of baricitinib to know is ACTT-2 (NEJM, 2021) which compared baricitinib + remdesivir to remdesivir alone in ~1,000 hospitalized patients with COVID-19 and found a significant improvement in the primary outcome of time to recovery. Only 11% of patients in ACTT-2 were on IMV or ECMO so very little was known prior to this new study about the utility of baricitinib in our sickest patients.

• As with the COV-BARRIER trial, most immunosuppressed patients were excluded. Exclusion criteria included the use of > 20mg prednisone daily, immunosuppressants, biologics, T-cell or B-cell targeted therapies, suspected serious active bacterial or fungal infection, or untreated TB. In my view, the use of baricitinib in immunosuppressed patients with COVID-19 (including patients with solid organ transplant) is a data-free zone. Use of baricitinib in this patient population should be on a case-by-case basis and should acknowledge that therapy might be harmful.

• Other important details about the study cohort
  • Only 3 patients in this trial were on ECMO. There is still much to learn about use of baricitinib in this setting
  • 86% of patients received steroids while only 2% received remdesivir.
  • Patients were hospitalized for a median of 4 days prior to randomization. Unfortunately, no information is provided on time from IMV or ECMO to enrollment.
• There were no significant differences in adverse events between the two arms including rates of infection and VTE.

• The RECOVERY Baricitinib trial just came out today in pre-print. It includes ~8K patients and also shows a reduction in 28-day mortality (12% vs 14%). Perhaps I will summarize this one in a later review.

• My take-away: I think the totality of evidence suggests that in non-immunosuppressed hospitalized patients with COVID-19 (including the critically ill) who have laboratory evidence of inflammation, the addition of baricitinib to dexamethasone likely improves mortality and does not seem to significantly increase rates of infection or VTE. While I don’t think this trial definitively proves that baricitinib improves mortality in patients on IMV or ECMO (the N is small, very few patients were on ECMO, and important details on timing of therapy are missing), it suggests we should not view IMV or ECMO as absolute contraindications to therapy.

Perkins et al. Effect of Noninvasive Respiratory Strategies on Intubation or Mortality among Patients with Acute Hypoxemic Respiratory Failure and COVID-19: The RECOVERY-RS Randomized Clinical Trial. JAMA 2022

Question: Does the use of CPAP or high-flow nasal oxygen (HFNO) compared to conventional oxygen therapy reduce the risk of invasive mechanical ventilation (IMV) or mortality at 30 days in patients with acute hypoxemic respiratory failure (AHRF) due to COVID-19?

Why ask it: The optimal mode and duration of non-invasive respiratory support in patients with AHRF due to COVID-19 is unknown.

Intervention: 1,273 patients with AHRF due to COVID-19 (defined as an SpO₂ £ 94% on ³ 0.4 FiO₂) hospitalized at 48 hospitals across the UK randomized to CPAP, HFNO, or conventional O₂ therapy with randomization informed by device availability at each trial site. Device interface, initial settings, titration, and need for IMV were left to the discretion of treating clinicians.

Results (absolute differences and 95% CIs not included for secondary outcomes for simplicity):

• Composite outcome of tracheal intubation or mortality within 30 days of randomization (primary outcome)
  • CPAP vs conventional O₂
    • 36.3% vs 44.4% (absolute difference, -8 [95% CI, -15% to -1%], p=0.03
  • HFNO vs conventional O₂
    • 44.3% vs 45.1% (absolute difference, -1% [95% CI, -8% to 6%], p=0.83
• CPAP with a lower rate of tracheal intubation vs conventional O₂ (33.4% vs 41.3%) but no difference in mortality at 30 days (16.7% vs 19.2%)
• CPAP with a lower frequency of admission to ICU vs conventional O₂ (55.4% vs 62.9%)
• CPAP with increased time to IMV compared to conventional O₂
  • 2.0 days (IQR 1.0 – 4.0) vs 1.0 day (IQR 0 – 4.0).
• No other statistically significant differences in other secondary outcomes between groups
• Post hoc comparison of primary outcome between CPAP and HFNO:
  • 34.6% vs 44.3% (absolute difference, -10% [95% CI, -18% to -2%], p=0.02)

Conclusion: In patients with AHRF due to COVID-19, the use of CPAP but not HFNO decreased the risk of a composite outcome of need for IMV or death at 30 days compared to the use of conventional O₂.

Comment:

• A parallel group, open-label, adaptive, 3-group RCT designed as essentially 2 separate RCTs (CPAP vs conventional O₂ and HFNO vs conventional O₂). This trial was not designed to robustly compare CPAP vs HFNO.
• Worth emphasizing that this was a pragmatic trial. Decisions regarding the device interface used, initial device settings, titration, and need for IMV were left to the treating clinician.
• The planned sample size was 4,002. The trial was stopped early due to declining hospitalization rates in the UK. This may have obscured the detection of smaller but still significant differences between study arms.
• Notable patient characteristics
  • Enrolled ~ 9 days from symptom onset
  • Median P/F at enrollment ~113
  • Mean initial CPAP 8.3 cmH₂O
  • Mean initial flow rate on HFNO 52.4 L/min
• Treatment crossover occurred in 17.1% of patients (most notably in 23.6% of patients randomized to conventional O₂). Findings from an inverse probability weighting analysis to account for crossover were consistent with the primary analysis.
• All 8 serious adverse events occurred in the CPAP group
• So, what do we do with this?
  • The idea that NIV may improve outcomes for patients with AHRF is not new. A systematic review and meta-analysis of 25 RCTs with 3,804 patients found that NIV was associated with lower rates of both IMV and mortality (Ferreyro et al. JAMA 2020)
  • However, several large cohort studies have shown that patients with more severe ARDS frequently fail NIV and those that do tend to have worse mortality (Bellani et al, AJRCCM 2016 as an example). Additionally, a post-hoc analysis of the FLORALI trial found that in immunocompromised patients, use of NIV was independently associated with an INCREASED risk of IMV and death (frat et al. Lancet Resp Med 2016).
  • ERS/ATS clinical practice guidelines offer no recommendation on the use of NIV in AHRF, stating a “trial of NIV might be offered to patients with AHRF, CAP, or early ARDS if they are managed by an experienced clinical team, carefully selected (no AMS, shock, MOF), are closely monitored in the ICU, reassessed early after starting NIV, and intubated promptly if they are not improving.”
  • It is critical that a decision to use NIV (or increase the frequency of its use in this patient population) needs to be considered in the context of local factors including RT staffing, ICU bed availability, device availability, and local practices. As an example, at NMH the use of CPAP would require an ICU bed outside of the ED (in contrast to the trial where CPAP decreased ICU utilization).
  • When considering all available evidence, I think both NIV and HFNO are reasonable initial support strategies in patients with AHRF. What matters is likely not what device as an absolute, but how well a specific device is paired with a specific patient in a specific care setting and how closely that patient is monitored for evidence of device intolerance or clinical deterioration.  Regardless of the device chosen, patients with a P/F < 150 should be monitored exceptionally closely as roughly 30 – 50% will fail non-invasive strategies and require IMV.

Yoshimura et al. Effect of Gram-stain Guided Initial Antibiotic Therapy on Clinical Response in Patients with Ventilator-associated Pneumonia: The GRACE-VAP Randomized Clinical Trial. JAMA Network Open 2022

Question: In patients with ventilator-associated pneumonia (VAP), is an empiric antibiotic strategy guided by Gram stain of an endotracheal aspirate non-inferior to antibiotics informed by 2016 IDSA guidelines?

Why ask it: VAP is a common complication of critical illness and associated with significant morbidity and mortality. Antibiotic selection is challenging as both under- and over-treatment of VAP may cause harm. There is conflicting data on whether Gram stain of a respiratory sample can safely inform antibiotic selection in patients with VAP.

Intervention: 206 patients diagnosed with VAP based on a modified Clinical Pulmonary Score ³ 5 at 12 centers in Japan randomized to Gram stain-guided antibiotics (see Comments for details) or guideline-based treatment.

Results (all written as Gram stain-guided group vs guideline-based group)

• Clinical response rate (primary outcome, see Comments for details)
  • 77% vs 72%, p < 0.001
• 28-day mortality
  • 14% vs 18%, p=0.44
• Median 28-day ventilator-free days
  • 22 vs 22, p=0.21
• Median 28-day ICU-free days
  • 19 vs 20, p=0.42
• Administration of anti-pseudomonal antibiotics
  • 70% vs 100%, p<0.001
• Anti-MRSA antibiotics
  • 61% vs 100%, p<0.001
• Coverage rate of initial antibiotic therapy
  • 86% vs 92%, p=0.18
• Antibiotic escalation
  • 7% vs 1%, p=0.03

Conclusion: In patients with VAP, Gram-stain-guided empiric antibiotics was non-inferior to guideline-based antibiotics with respect to clinical response assessed 7 days after the end of therapy

Comment:

• This was a multicenter open-label noninferiority trial with blinded endpoint assessment. Unblinding of the treating team was necessary due to the nature of the intervention
• Notable exclusions
  • Heart failure or atelectasis diagnosis
  • Receipt of antibiotics for > 24 hrs after meeting inclusion criteria
  • Infection with COVID-19
• Additional study procedure details (picture also pasted below)
  • Endotracheal aspirate (not a true alveolar sample) used for Gram stain and culture
  • Antibiotic selection in gram stain group
    • GPCs in chains and/or gram-positive bacilli: non-pseudomonal b-lactam
    • GPCs in clusters without GNRs: Anti-MRSA agent
    • GNRs without GPCs in clusters: Anti-pseudomonal agent
    • GPCs in clusters and GNRs: Anti-MRSA agent + anti-pseudomonal agent
    • Negative Gram stain: Anti-MRSA agent + anti-pseudomonal agent
  • Antibiotic selection in guideline-based group
    • Anti-MRSA + single anti-pseudomonal agent (authors note 80-90% of their P. aeruginosa isolates are susceptible to an anti-pseudomonal b-lactam so they did recommend empiric double coverage)
  • Antibiotics were administered for at least 7 days
• Primary outcome = “clinical response rate” assessed 7 days after end of therapy. Clinical response defined as all of the following
  • Completion of antibiotics within 14 days
  • Improvement or lack of progression of baseline radiographic findings at the end of therapy
  • Resolution of signs and symptoms of pneumonia
  • Lack of antibiotic re-administration owing to pneumonia by the follow-up or test of cure visit
• The study enrolled 206 out of 208 patients assessed (!!!)
• The study met their proposed sample size of 100 patients per group (informed by an assumed clinical response rate of 68% and a 20% noninferiority margin)
• Notable patient characteristics
  • Men: 69%
  • Trauma: 27%
  • Post-arrest: 24%
  • Stroke: 10%
  • Immunocompromised: 3%
  • Previous antibiotics: 28%
  • Sepsis: 34%
  • Median number of days from ICU admission to randomization: 4
• Most common isolated pathogens:
  • Staphylococcus aureus: 50% (21% of which were MRSA)
  • Klebsiella spp: 17%
  • H influenza: 8%
  • Other notables
    • P. aeruginosa: 5%
    • ESBL-producing Enterobacteriaceae: 3%
    • MDR Gram-negatives: 0
  • It’s not clear to me from data tables how many samples were culture-negative or how many had polymicrobial growth. 14/206 had a negative Gram stain
• Test characteristics of Gram stain
  • S. aureus
    • Sensitivity 84% and specificity 76%
  • GNRs
    • Sensitivity 83% and specificity 61%
• In subgroup analysis, there was significant heterogeneity in the effect of Gram stain-guided antibiotics in patients with TBI with better clinical response rates seen in Gram stain-guided antibiotics
• Numerically more diarrhea in guideline-based group (27 vs 38)
• Only 4 cases of C.diff (1 in Gram stain-guided group)
• My take
  • The main issue is generalizability to our practice
    • This study included a lot of patients with trauma and stroke, relied on endotracheal aspirates, had low rates of infection with P. aeruginosa and resistant GNRs, and did not incorporate PCR-based diagnostics.
    • We care for many more immunocompromised patients, perform early alveolar sampling in most patients with suspected VAP, and have access to multiplex PCR-based diagnostics. In our alveolar samples, a high % are culture-negative and P. aeruginosa is the most common bacterial pathogen identified (thanks to Cathy Gao and Marjorie Kang for this data)
    • In this context, I would be hesitant to discontinue anti-MRSA or anti-pseudomonal antibiotics based on Gram stain alone (I would instead wait for the PCR). The results of a Gram stain may add some secondary support to a de-escalation decision informed primarily by PCR testing.
    • Use of Gram stain to guide antibiotics may be of use to clinicians in settings without access to PCR-based testing depending on local microbiology and resistance patterns
    • How to use PCR-based diagnostics to inform antibiotic selection in severe pneumonia is a major area of research (including at NM)
  • Our group has looked at Gram stain to rule-out culture-positive HAP/VAP and found that the combination of a BAL neutrophil threshold of < 50% + a negative Gram stain had a negative predictive value of nearly 100% (Walter, AJRCCM 2018)