Examples of systematic reviews

Goran Poropat

Cochrane systematic reviews

To make unmanageable amounts of information – manageable

Identify, appraise and synthesize research-based evidence

Present in an accessible format

Cochrane systematic reviews

Clearly stated set of objectives

Explicit, reproducible methodology

Systematic search

Assessment of validity

Systematic presentation

Protocol for a Cochrane review

Idea

Register title

Write protocol

To minimize the potential for bias in the review process

Changes possible

Bezafibrate for primary biliary cirrhosis 

Title* Protocol information: Authors* Contact person* Dates What’s new History The protocol: Background* Objectives* Methods: Criteria for selecting studies for this review: Types of studies* Types of participants* Types of interventions* Types of outcome measures*

Search methods for identification of studies* Data collection and analysis* Acknowledgements References: Other references: Additional references Other published versions of this review Tables and figures: Additional tables Figures

Supplementary information: Appendices Feedback: Title Summary Reply Contributors About the article: Contributions of authors Declarations of interest* Sources of support: Internal sources External sources Published notes

Bezafibrate for primary biliary cirrhosis

Bezafibrate for primary biliary cirrhosis

• Chronic, progressive, inflammatory and autoimmune-mediated liver disease

• Survival in symptomatic patients = 10-15 yr.

• Bilirubin – indipendent predictor of survival and prognosis

• Bezafibrate – inhibition of acetil-CoA carboxylase activity• PPAR - ATP-binding cassette (ABC) B4 transporter• Increased secretion of phosphatidyl-choline

Bezafibrate for primary biliary cirrhosis

MethodsTypes of studies

• RCTs assessing bezafibrate in patients with PBC• Irrespective of blinding, language, publication status• Quasi-randomised and observational studies

– Exluded for report of benefit– Included for report of harm

Bezafibrate for primary biliary cirrhosis

Types of participants• Pts with PBC

– Elevated alkaline phophatases– Positive anti-mitochondrial antibody– Compatible liver biopsy

Types of interventions – bezafibrate at any dose or regimen vs.placebo or any other drug

Bezafibrate for primary biliary cirrhosis

Types of outcome measures

Bezafibrate for primary biliary cirrhosis

Search methods of identification of studies• Cochrane Hepato-Biliary Group Controlled Trials Register• The Cochrane Central Register of Controlled Trials (CENTRAL)

in the Cochrane Library• MEDLINE• EMBASE• Science Citation Index Expanded• LILACS• Chinese Bio-medical Literature Database

• Reference lists of identified studies• Pharmaceutical companies• Clinicaltrials.gov• WHO International Clinical Trials Registry Platform

Bezafibrate for primary biliary cirrhosis

Data collection and analysis• Two authors independently • Disagreements resolved by discussion

Risk of bias assessment• Allocation sequence generation• Allocation concealment• Blinding• Incomplete outcome data• Selective outcome reporting• Other bias

Bezafibrate for primary biliary cirrhosis

Statistical analyses• Fixed-effect and random-effect models meta-analyses

• Dichotomous outcomes – RR/RD (95% CI)• Continuous outcomes – MD (95% CI)

• Dichotomous outcomes – intention-to-treat• Continuous outcomes – case analysis and inclusion of known data

• Assesment of heterogeneity (chi-square test)

• Trial sequential analysis

Search results

91 PUBLICATIONS IDENTIFIED

65 PUBLICATIONS ASSESSED

7 PUBLICATIONS INCLUDED

6 TRIALS INCLUDED

26 DUPLICATES

58 PUBLICATIONS EXCLUDED

4 TRIALS (N=82)Bezafibrate vs. no intervention

2 TRIALS (N=69)Bezafibrate vs. UDCA

Characteristics of included studies

• All trials from Japan

• Parallel groups design (5 trials)• Cross-over design (1 trial)

• >85% participants were female

• Non-advanced PBC (4 trials)• PBC stage not known (2 trials)

Characteristics of included studies

• Bezafibrate 400 mg daily orally

• Duration of administration of bezafibrate– 6 moths (2 trials)– 12-13 months (4 trials)

• UDCA 600 mg daily orally

Risk of bias judgement

All six trials are at high risk of bias

Results:Trials assessing bezafibrate vs. no

intervention

LIVER-RELATED MORBIDITY

ALL-CAUSE MORTALITY

PRURITUS

ADVERSE EVENTS

ALKALINE PHOSPHATASES

MD -186, 95% CI -249 to -123; I2 = 34%

Trial sequential analysis (ALP)

A minimal relevant difference 100 U/L(based on clinical judgement, more modest than the estimated effect seen in the meta-analysis)

Standard deviation 200 U/L

Risk of type I error 5%

Risk of type II error 20%

Required information size 216

TSA – ALKALINE PHOSPHATASES

Other results

IgMBilirubin

GTALT

Total cholesterolTryglicerids

No effect on

ConclusionBezafibrate vs. no intervention

• No significant effect on mortality, liver-related morbidity, adverse events, and pruritus

• Quality of life and fatigue could not be assessed

• Trial sequential analysis implies evidence for a beneficial effect on serum alkaline phosphatases activity

Results:Trials assessing bezafibrate vs. ursodeoxycholic acid (UDCA)

LIVER-RELATED MORBIDITY

ALL-CAUSE MORTALITY

ALKALINE PHOSPHATASES

ADVERSE EVENTS

Other results

Fixed-effect analysis

Random-effect analysis

Significant decrease of ALP, GT, ALT, IgM

No effect on GT, ALT, IgM

ConclusionBezafibrate vs. UDCA

• No significant effect on mortality, liver-related morbidity, adverse events, and pruritus

• Quality of life, pruritus, and fatigue could not be assessed

• There is no firm evidence of effect on ALP, GT, ALT, and IgM

CONCLUSIONS

Treatment of primary biliary cirrhosis with

bezafibrate can neither be supported nor rejected