urrn all R hiin ollo Systemic corticosteroids for acute sinusitis (Review) ene amp P RP t a, Acute sinusitis

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1 Journal Rhinology PICO P : patients with acute rhinosinusitis I : systemic corticosteroids C : placebo O : improvement of symptoms พญ.ว พรร ณ ฐร งส Advisor : อ.ส รพล ซ อตรง อ.ว ส ตร ร ช ยพ ช ตก ล Systemic corticosteroids for acute sinusitis (Review) Venekamp RP et al, The Cochrane Library 2011,, Issue 12 Background Acute sinusitis : 50 case/year ATB rates in daily practice ( %) ATB : limited use in acute sinusitis (Ahovuo-Saloranta 2011; Young 2008) Health care costs and ATB resistance Acute sinusitis Diagnosis : signs and symptoms Etiology of acute sinusitis -Bacterial infection of PNS (Piccirillo 2004) - Viral : majority of cases (0.5-2% complicated by bacteria): - (Berg 1986, Gwaltney 1996) 1

2 Corticosteroids AR and local eosinophilia : may play important role. (Baroody 2008; Kirtsreesakul 2004) Anti nti-inflammatory inflammatory Tx - host inflammatory response - mucosal edema - sinus clearance Inhibit transcription of pro-inflammatory mediators in human airway endothelial cells (Mygind 2001) Act as anti-inflammatory inflammatory and decongestant agents INCS Acute sinusitis : no overall beneficial effect (Zalmanovici 2011; Williamson 2007) More effective in mild cases Thick secretions and severe inflammation limit topical delivery Systemic corticosteroids Might allow more effective delivery severity of some acute URI - Croup (Russell 2011) - Sore throat (Hayward 2009) - Asthma & COPD exacerbation (Schweiger 2010) Objectives Contraindications - (Active) PU - Hx of depression or psychosis -Immunodeficiency To assess effectiveness of systemic CS on clinical response rates in children and adults with acute sinusitis To determine adverse effects & relapse rates of Tx with systemic CS compared to placebo or standard clinical care 2

3 Methods Types of studies : RCT Types of participants Children & adults with acute sinusitis. Dx : clinical +/- film or nasal endoscopy Exclude -Chronic sinusitis (> 12 wk) -Other clear Dx (common cold, nasal polyposis) Types of interventions Systemic CS (oral, i.v., i.m.) VS placebo or standard clinical care Co-Tx : ATB Exclude : intranasal route or inhalation Types of outcome measures Primary outcomes - Proportion of pt with resolution or improvement of symptoms - Short-term term (< 2 wk) or long-term (> 2 wk) Secondary outcomes - Time lapse before resolution of symptoms - Relapse rates - Adverse events Search methods Electronic searches Cochrane Central Register of Controlled Trials (CENTRAL) 2011, Issue 2 MEDLINE ( ) EMBASE ( ) Reference lists of all studies Data collection and analysis Selection of studies 2 review authors : screened titles and abstracts and reviewed full text Assessment of risk of bias Methodological quality of studies - Random sequence generation - Allocation concealment - Blinding - Completeness of data - Outcome assessment 3

4 Measures of treatment effect Intention-to-treat treat (ITT) analyses Dichotomous outcomes - risk ratios (RR) - risk difference (RD) - 95% CI Dealing with missing data Contact trial authors Primary analyses : only available data by performing scenario analyses (best and worst-case scenario) Assessment of heterogeneity I 2 statistic to measure statistical heterogeneity for each outcome - No heterogeneity fixed-effect effect meta- analysis - Substantial heterogeneity (I 2 > 50%) random-effects model Sensitivity analysis Remove single trials to investigate extent to which they contributed to heterogeneity Results Total 2630 studies Removing duplicates 1710 Screening : 7 potentially eligible Exclude 3 trials (CRS) 4 trials eligible for inclusion : Cannoni 1990; Gehanno 2000; Klossek 2004; Ratau

5 Included studies Total 1008 participants : adults Ratau 2004 : primary care clinics in South Africa (clinically Dx sinusitis) Cannoni i , Gehanno 2000, Klossek 2004 : ENT OPD in France (+ + radiologcal assessment) Interventions Oral (methyl) prednisone ( mg) for 3,5,7 days and oral betamethasone 1mg for 5 days Control group - Placebo (Gehanno 2000 ; Klossek 2004; Ratau 2004) - NSAID (Cannoni 1990) Co-intervention All participants in 4 studies : oral ATB - amoxicillin-clavulanic clavulanic acid (Gehanno 2000; Ratau 2004) -cefpodoxime (Klossek 2004) - pristinamycin (Cannoni 1990) Other medication Acetaminophen/paracetamol) : Klossek 2004; ; Ratau 2004 No symptomatic relief med : Cannoni 1990 No information : Gehanno 2000 Result report Adverse events Cannoni 1990 Gehanno 2000 Klssek 2004 Therapeutic success Pain relief Global response to Tx Day 7 Day 4 Day 3 and day Cannoni 1990, Klossek 2004 : pt (questionnaire) and investigator (at visits) Gehanno 2000 : investigator Ratau 2004 : patients Ratau 2004 improvement of symptoms & physical signs present or absent Day 0-6 5

6 Risk of bias in included studies Methodological quality : moderate Allocation -Randomisation but no concealment of allocation - Cannoni 1990, Gehanno 2000, Klossek 2004 : unclear methods of randomisation - Klossek 2004 : baseline characteristics of pt Blinding 4 trials : double-blinded blinded Insufficient detail : participants, outcome assessors or study personnel Incomplete outcome data Cannoni 1990, Gehanno 2000, Klossek 2004 : Number of drop out Ratau 2004 : not reported (assumed no drop-outs) outs) Total pt lost to F/U Klossek 2004 : 8% (Tx gr >) Gehanno 2000 : 4% (Tx gr >) Cannoni 1990 : 7% (control gr >) Selective reporting Gehanno 2000, Klossek 2004 : ITT analysis Cannoni 1990, Ratau 2004 : not clear Primary outcomes Pt with resolution or improvement of symptoms 2 effect estimates - Days 3-7 -Days 4-10 or 12 6

7 Pt tx with oral CS : more likely to have short-term term resolution or improvement of symptoms than control (placebo or NSAIDs) Days 3-7 : RR 1.4, 95% CI , RD 20% (6-34%) Day 4-10/1212 : RR 1.3, 95% CI , RD 18% (3-33%) Statistical heterogeneity : high in both analyses (I2 statistic 75%%) %) sensitivity analysis (remove trial with NSAIDs) Similar effect but lesser extent Days 3-6 : RR 1.2, 95% CI , RD 12% (5-19%) Days 4-10/1212 : RR 1.1, 95%CI , RD 10% % (3-16%) Scenario analyses Beneficial effect of oral CS Best case : effect sizes Worst-case : no statistically significant effect Long-term effects (>2 wk) : no data Secondary outcomes Time lapsed before resolution of symptoms : no o data Adverse events - No serious adverse events -Mild adverse events (abdominal pain, diarrhoea) and discontinuation between CS and placebo groups : Gehanno 2000, Klossek 2004, Ratau

8 Adverse events Ratau 2004 : 7 severe adverse events -3 in CS : diarrhoea, acute gastroenteritis, abdominal pain - 4 in placebo : vomiting, abdominal pain, neuralgia ear pain Cannoni 1990 Adverse events - NSAID : 51 in 35 pt - CS : 23 in 18 pt NSAID gr : discontinuation of 7 pt Discussion Bacteria a C/S and relapse rates : No data Subgroup analysis Tx effect of oral CS : larger at short-term term time point (Days 6-7) )th than at very short- term (Days 3-4) Summary of main results Acute sinusitis pt Tx with oral CS : short- term improvement or resolution of symptoms than control Tx (placebo or NSAIDs) at Days 3-7 SE : limited and mild Overall completeness and applicability of evidence 4 studies & limited number of pt Effectiveness of oral CS : only up to Day Long-term (> 2 wk) effects : unclear Relapse rates of acute sinusitis : unknown All pt in 4 studies : also oral ATB Majority of pt : in ENT OPD Quality of the evidence Moderate method quality : biased estimates of effect None : adequately reported blinding procedure 3 studies : complete case- analysis (excluding lost pt) validity 8

9 Potential biases in the review process Some clinical heterogeneity Dx : clinical +/- radio Duration, dose of intervention, type of control, F/U time :vary Different outcome assessments : invalid results Results of 4 studies : practically equal Agreements and disagreements with other studies or reviews No previous review on use of systemic CS in acute sinusitis Valid comparison cannot be made Author s conclusions Implications for practice -Oral CS as adjunctive Tx to oral ATB : effective in short-term term relief of symptoms in acute sinusitis - Limited data and significant risk of bias Implications for research -High-quality trials assessing efficacy of systemic CS both as adjuvant and monotherapy in primary care setting Report short term (< 2 wk) &long-term (> 2 wk) effects, relapse rates, adverse events Thank you 9