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Journal Club; Wednesday January 18, 2017– Anna Yee
Effect of Corticosteroids on Treatment Failure Among Hospitalized Patients With Severe Community-Acquired Pneumonia and High
Inflammatory Response A Randomized Clinical Trial
Torres A, Sibila O, Ferrer M, Polverino E, Menendez R, Mensa J et al. Effect of Corticosteroids on Treatment Failure Among Hospitalized
Patients With Severe Community-Acquired Pneumonia and High Inflammatory Response. JAMA. 2015;313(7):677.
Background
Mortality among patient with severe community acquired pneumonia (CAP) is high, especially in those who
experience treatment failure. This maybe a result of an excessive host inflammatory response. Corticosteroids reduce
inflammation by modulating cytokine release in these patients.
Rationale
The use of corticosteroids in patients with CAP is controversial with studies showing conflicting data. Two metaanalyses found mortality benefit with corticosteroid use in a subgroup of patients with severe CAP.
Objective
To determine whether patients with severe community acquired pneumonia and a high inflammatory response
would benefit from corticosteroids, using treatment failure as a surrogate parameter for mortality,
Trial Design
Multi-centered, double-blind, placebo controlled RCT
Population
N= 120 Men and women with severe CAP and a high inflammatory response at 3 Spanish teaching schools
Eligibility
Inclusion Criteria:
 Age ≥ 18
 Clinical symptoms suggesting CAP
(cough, fever, pleuritic chest pain,
or dyspnea)
 New chest radiographic infiltrate
 Met severe CAP criteria (defined by
modified American Thoracic Society
criteria or PSI class V
 CRP > 150 mg/L at admission
Intervention
Exclusion Criteria:
 Prior treatment with systemic corticosteroids
 Nosocomial pneumonia
 Severe immunosuppression (HIV, immunosuppressive condition or
medications)
 Preexisting medical condition with a life expectancy <3 months
 Uncontrolled diabetes mellitus
 Major GI bleed within 3 months
 Condition requiring acute treatment with > 1mg/kg/d of
methylprednisolone or its equivalent
 Pandemic H1N1 influenza A pneumonia
IV methylprednisolone 0.5mg/kg q12h vs placebo x 5 days within 36h of admission
Outcomes
Primary Endpoints:
 Efficacy: rate of treatment failure (early, late or at both times)
o Early treatment failure: clinical deterioration within 72 hours of
treatment
o Late treatment failure: radiographic progression, persistence of
severe respiratory failure, development of shock, need for
invasive mechanical ventilation not present at baseline or death
between 72-120 hours after treatment initiation
Statistics
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Results –
baseline
characteristics
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Secondary Endpoints:
 Time to clinical stability (Temp ≤
37.2°C, HR ≤ 100 bpm, SBP ≥
90mmHg, arterial oxygen tension ≥
60mmHg without oxygen
supplementation)
 Length of ICU and hospital stays
 In-hospital mortality
N = 120 for 80% power with a 2 sided type I error of 0.05 to detect an absolute 20% reduction in treatment
failure by methylprednisolone vs. placebo
Based on the results of a previous study where the same investigators found a 35% treatment failure rate in
placebo group and 15% total treatment failure rate
Prespecified interim analysis planned at 50% of patient accrual, where p-value <0.03 was needed to maintain an
overall Type I error of 0.05 for interim and final analyses
Both intention to treat (at least 1 dose of study drug) and per-protocol analysis (at least 6 doses of study drug
and did not have serious deviations from protocol)
Sensitivity analysis using logistic regression model
~65 y/o, majority male
Placebo: more chronic pulmonary disease and CHF, higher procalcitonin, IL 6, 8 and 10, mechanical ventilation
and septic shock, ICU admission
Treatment: higher CRP
Only ~ 1/3 of patients had PSI Risk class V
Time to first antibiotic dose similar; 30% patients with septic shock received within 1 hr, 30-50% within 1-4 hrs
Majority started on ceftriaxone/levofloxacin combo or ceftriaxone/azithromycin (unknown dose) for average 10
days
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Journal Club; Wednesday January 18, 2017– Anna Yee
Results (ITT)
Methyl
prednisolone
Placebo
Unadjusted HR
(95% CI)
P-value
Adjusted HR
(95% CI)
P-value
Primary Outcome
Treatment failure
8 (13)
18 (31)
0.34 (0.14-0.87) 0.02
0.33 (0.12-0.90) 0.03
(%)
Early treatment
6 (10)
6 (10)
0.96 (0.29-3.18) 0.95
1.14 (0.28-4.67) 0.86
failure (%)
Late treatment
2 (3)
15 (25)
0.10 (0.02-0.46) 0.003
0.09 (0.02-0.47) 0.004
failure (%)
Secondary outcomes
Time to clinical
4 (3-6)
5 (3-7)
1.16 (0.78-1.73) 0.46
1.11 (0.72-1.71) 0.64
stability (IQR), days
Length of ICU stay
5 (3-5)
6 (4-8)
0.18 (0.02-1.46) 0.11
0.13 (0.01-1.44) 0.10
(IQR), days
Length of hospital
11 (7.5-14)
10.5 (8-15)
0.66 (0.23-1.85) 0.43
0.61 (0.19-1.93) 0.40
stay (IQR), days
In hospital
6 (10)
9 (15)
0.61 (0.20-1.82) 0.37
0.57 (0.16-2.00) 0.38
mortality (%)
 Absolute reduction of 18%
 Overall treatment failure driven by late treatment failure, specifically radiographic progression
 ADRs: more hyperglycemia in treatment group, relatively low incidence of other ADRs
Generalizability  Criteria to determine severe CAP were based on validated international guidelines
 Multi-centered out of Spain, majority required ICU admission
 15 patients in total required mechanical ventilation (noninvasive & invasive); different from our ICU population
 Dosing of methylprednisolone is comparable to COPD dosing (60 -120 mg/d), but agent, dose and duration was
different from studies included in the meta-analysis (which also varied in agent, dose and duration)
 Using CRP > 150mg/L for inclusion was 25th percentile of patients with CAP in another study, suggesting
majority of patients with CAP have an inflammatory response
Randomization/  Randomization based on a 1 to 1 allocation of pre-number boxes containing dosing unit and with identical
Allocation bias
appearance for methylprednisolone and placebo
 Placebo group may potentially have sicker patients, which may result in more treatment failure
Blinding
 All patients, investigators and data assessors were blinded to treatment allocation
Attrition Bias
 No loss to follow up
 ITT and Per-protocol analyses used, and sensitivity analysis performed
Reporting Bias
 Outcomes assess rate of treatment failure, which was a surrogate parameter determined from a previous study
by same authors, where they found that patients with treatment failure had higher morality
 In-hospital mortality was a secondary outcome, which the study was not powered to detect
 ADRs were not included as primary or secondary outcomes
Other
 Used 2 severity scales for inclusion criteria – did not use both on all patients; severity of patient population
questionable
 Only 1 incidence of superinfection reported, but from CORTICUS study high incidence of superinfections
 Did not use procalcitonin to guide antibiotic therapy/duration
 Treatment with antibiotics based on international guidelines, but did not set up rules for antibiotic use and
dosing; unknown if empiric treatment was narrowed
 Assessment of radiologic progression is subjective
Conclusion
 Author’s conclusion: acute use of methylprednisolone compared with placebo decreased treatment failure
 My conclusion: given the limitations of this study, we cannot confidently say that corticosteroids lower the rate
of treatment failure in patients with severe CAP. It is also unknown whether reduction in treatment failure is
associated with reduction in mortality.
Application to
 More studies are needed to determine the clinical utility of corticosteroids with outcomes that would have a
Clinical Practice
practical impact, including mortality, hospital/ICU length of stay, antibiotic usage and duration etc.
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Journal Club; Wednesday January 18, 2017– Anna Yee
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Journal Club; Wednesday January 18, 2017– Anna Yee
American Thoracic Society Criteria
Admission into ICU would require
 At least one major criteria
 At least 3 minor criteria
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