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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 Results – baseline characteristics 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 1 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. 2 Journal Club; Wednesday January 18, 2017– Anna Yee 3 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 4