CINeMA Georgia Salanti & Theodore Papakonstantinou Institute of - PowerPoint PPT Presentation

CINeMA Georgia Salanti & Theodore Papakonstantinou Institute of Social and Preventive Medicine University of Bern Switzerland

The most critical question raised by patients and clinicians at the point of care is “what is the drug of choice for the given condition?” Del Fiol G et al. Clinical questions raised by clinicians at the point of care: a systematic review. JAMA Intern Med. 2014

Leucht S et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia. Lancet 2013 AMI ARI ZOT ZIP ASE SER CLO CPZ RIS QUE HAL ` ILO ` PBO LURA PAL OLA

AMI AMI Indirect treatment effect Direct treatment RIS effect OLA OLA

AMI Indirect treatment effect Direct treatment RIS effect Network or Mixed treatment effect OLA

Leucht S et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia. Lancet 2013 AMI ARI ZOT ZIP ASE SER CLO CPZ RIS QUE HAL ` ILO ` PBO LURA PAL OLA

456 published networks in the medical literature comparing at least 4 medical interventions (March 2015) (Petropoulou et al. Journal of Clinical Epidemiology 2016, Zarin et al. BMC Medicine 2016) 120 Number of published networks of interventions 100 80 60 40 20 0 1997 1999 2000 2002 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Y ear of publication

None of the 456 NMAs published until 3/2015 attempted to evaluate the confidence in NMA results!

CINeMA framework Consider the network estimates Study limitations Rate each network estimate Indirectness No concerns Inconsistency (heterogeneity, incoherence) Some concerns Imprecision Major concerns Publication bias Network Study Indirectness Inconsistency Imprecision Publication Confidence estimate limitations bias Heterogeneity Incoherence A vs B Some Some Major Some Some undetected Very low concerns concerns concerns concerns concerns A vs C No No concerns No concerns Major No concerns suspected Low concerns concerns ….

Methods developed by: Georgia Salanti Julian Higgins Adriani Nikolakopoulou Web developer: Theodore Papakonstantinou Project supervision: Matthias Egger

Number of studies 22 Number of treatment nodes 6 Effect of antihypertensives on incidence diabetes mellitus - Primary outcome proportion of patients who developed diabetes Measurement Binary Intervention comparison type pharmacological vs placebo

CONFIDENCE MODERATE MODERATE Semi-automated process MODERATE LOW MODERATE Explicit rules that classify each network meta- LOW analysis effect for each domain to MODERATE No concerns, Some concerns, Major concerns VERY LOW as described in the documentation MODERATE MODERATE VERY LOW The rules can be overwritten! MODERATE LOW LOW LOW

CINeMA The aim of the webinar is to explain the methods used in CINeMA and present an alpha version of the web application pollev.com/gmhbe

q Major concerns q Some concerns q No concerns

Form risk of bias judgements for each study. Consider selection, performance, attrition, detection and reporting bias Study name Risk of Bias AASK LOW ALLHAT LOW ALPINE LOW ANBP-2 LOW ASCOT LOW CCB vs Diuretics: CAPPP MODERATE CHARM LOW overall low risk of bias DREAM LOW EWPHE MODERATE FEVER LOW HAPPHY HIGH HOPE LOW INSIGHT LOW INVEST LOW LIFE LOW MRC LOW NORDIL LOW PEACE LOW SCOPE MODERATE SHEP LOW STOP-2 MODERATE VALUE MODERATE Plot direct comparison in green

OR from NMA Comparison BB vs Placebo Diuretics CCB ACE ARB Diuretics vs BB CCB ACE ARB CCB vs Diuretics ACE ARB ACE vs CCB ARB ARB vs ACE 0.4 0.7 1 1.5 2 Favors first

OR from NMA Comparison BB vs Placebo Diuretics CCB ACE ARB Diuretics vs BB CCB ACE ARB CCB vs Diuretics ACE ARB ACE vs CCB ARB ARB vs ACE 0.4 0.7 1 1.5 2 Favors first

OR from NMA Comparison BB vs Placebo Diuretics What is your judgement about study limitations for CCB ACE this (mixed) OR between CCB vs Diuretics estimated ARB in network meta-analysis? CCB q Major concerns ACE ARB q Some concerns CCB vs Diuretics q No concerns ACE ARB ACE vs CCB Go to: ARB pollev.com/gmhbe ARB vs ACE 0.4 0.7 1 1.5 2

BB vs Placebo Diuretics CCB ACE ARB Diuretics vs BB CCB ACE Studies with high risk of bias ARB contribute to the estimation of CCB vs Diuretics ! ACE ARB the OR CCB vs Diuretics! ACE vs CCB ARB ARB vs ACE 0.4 0.7 1 1.5 2

OR from NMA Comparison What is your judgement about study limitations for BB vs Placebo Diuretics this (indirect) OR for ACE vs ARB estimated in NMA? CCB ACE ARB q Major concerns Diuretics vs BB q Some concerns CCB ACE ARB q No concerns CCB vs Diuretics ACE ARB ACE vs CCB ARB ARB vs ACE 0.4 0.7 1 1.5 2 Favors first

An indirect or mixed treatment effect is a combination of the available direct treatment effects The contribution matrix ACE: ACE: ACE: ACE: ARB: ARB: ARB: ARB: BBlocker: BBlocker: BBlocker: CCB: CCB: Diuretic: BBlocker CCB Diuretic Placebo BBlocker CCB Diuretic Placebo CCB Diuretic Placebo Diuretic Placebo Placebo Mixed estimates 32 10 10 8 6 1 0 4 15 6 2 5 2 0 ACE:BBlocker 10 26 13 11 1 6 0 4 9 1 0 13 6 0 ACE:CCB 6 7 57 5 0 2 0 2 1 5 0 12 2 2 ACE:Diuretic 5 7 5 56 3 3 0 6 1 0 2 3 8 2 ACE:Placebo 4 1 0 3 41 21 0 5 19 2 2 2 1 0 ARB:BBlocker 1 2 1 2 8 67 0 6 8 1 0 2 4 0 ARB:CCB 3 2 11 5 10 27 0 8 0 7 0 25 0 2 ARB:Diuretic 3 3 2 7 6 15 0 49 0 1 2 2 10 1 ARB:Placebo 6 4 1 1 11 12 0 0 53 4 2 5 2 0 BBlocker:CCB 10 1 13 2 5 3 0 2 19 20 2 21 0 2 BBlocker:Diuretic 10 2 2 14 13 3 0 16 16 4 8 1 11 2 BBlocker:Placebo 2 6 11 3 1 3 0 2 7 6 0 56 3 2 CCB:Diuretic 2 6 4 12 1 15 0 16 6 0 2 5 28 2 CCB:Placebo 0 0 20 20 2 7 0 9 0 5 2 17 11 7 Diuretic:Placebo Indirect estimates 10 11 8 16 11 20 0 14 1 1 0 7 2 0 ACE:ARB

An indirect or mixed treatment effect is a combination of the available direct treatment effects The contribution matrix ACE: ACE: ACE: ACE: ARB: ARB: ARB: ARB: BBlocker: BBlocker: BBlocker: CCB: CCB: Diuretic: BBlocker CCB Diuretic Placebo BBlocker CCB Diuretic Placebo CCB Diuretic Placebo Diuretic Placebo Placebo Mixed estimates 32 10 10 8 6 1 0 4 15 6 2 5 2 0 ACE:BBlocker 10 26 13 11 1 6 0 4 9 1 0 13 6 0 ACE:CCB 6 7 57 5 0 2 0 2 1 5 0 12 2 2 ACE:Diuretic 5 7 5 56 3 3 0 6 1 0 2 3 8 2 ACE:Placebo 4 1 0 3 41 21 0 5 19 2 2 2 1 0 ARB:BBlocker 1 2 1 2 8 67 0 6 8 1 0 2 4 0 ARB:CCB 3 2 11 5 10 27 0 8 0 7 0 25 0 2 ARB:Diuretic 3 3 2 7 6 15 0 49 0 1 2 2 10 1 ARB:Placebo 6 4 1 1 11 12 0 0 53 4 2 5 2 0 BBlocker:CCB 10 1 13 2 5 3 0 2 19 20 2 21 0 2 BBlocker:Diuretic 10 2 2 14 13 3 0 16 16 4 8 1 11 2 BBlocker:Placebo 2 6 11 3 1 3 0 2 7 6 0 56 3 2 CCB:Diuretic 2 6 4 12 1 15 0 16 6 0 2 5 28 2 CCB:Placebo 0 0 20 20 2 7 0 9 0 5 2 17 11 7 Diuretic:Placebo Indirect estimates 10 11 8 16 11 20 0 14 1 1 0 7 2 0 ACE:ARB

The contribution matrix ACE: ACE: ACE: ACE: ARB: ARB: ARB: ARB: BBlocker: BBlocker: BBlocker: CCB: BBlocker CCB Diuretic Placebo BBlocker CCB Diuretic Placebo CCB Diuretic Placebo Diuretic Mixed estimates 32 10 10 8 6 1 0 4 15 6 2 5 ACE:BBlocker 10 26 13 11 1 6 0 4 9 1 0 13 ACE:CCB 6 7 57 5 0 2 0 2 1 5 0 12 ACE:Diuretic 5 7 5 56 3 3 0 6 1 0 2 3 ACE:Placebo 4 1 0 3 41 21 0 5 19 2 2 2 ARB:BBlocker 1 2 1 2 8 67 0 6 8 1 0 2 ARB:CCB 3 2 11 5 10 27 0 8 0 7 0 25 ARB:Diuretic 3 3 2 7 6 15 0 49 0 1 2 2 ARB:Placebo 6 4 1 1 11 12 0 0 53 4 2 5 BBlocker:CCB 10 1 13 2 5 3 0 2 19 20 2 21 BBlocker:Diuretic 10 2 2 14 13 3 0 16 16 4 8 1 BBlocker:Placebo 2 6 11 3 1 3 0 2 7 6 0 56 CCB:Diuretic 2 6 4 12 1 15 0 16 6 0 2 5 CCB:Placebo 0 0 20 20 2 7 0 9 0 5 2 17 Diuretic:Placebo Indirect estimates 10 11 8 16 11 20 0 14 1 1 0 7 ACE:ARB 10 11 8