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“Evidence-Based Medicine”Therapy

‘ ‘Evidence-Based Medicine’Evidence-Based Medicine’

‘ ‘Critical Appraisal’Critical Appraisal’

Research MethodologyResearch Methodology

Health ServicesHealth Services

“Evidence-Based Medicine”(Papers in Journal of Medicine / Health Sciences)

‘Valid’ Methodology of study

‘Important’ Result of study

‘Applicability’ Discussion

‘VIA’

Treatment / Therapeutic intervention

EBM : Valid, important and applicable to particular patients

High rank of hierarchy of evidence(Systematic reviews /meta-analyses;

Randomized Controlled clinical trial / RCT)

Treatment / Therapeutic intervention

Answerable Clinical Question (ACQ)

P : Patient, Problem, Population I : InterventionC : ComparisonO : Outcome

Hypertensive patient – should I start ACE inhibitors?

Patient : middle aged man with diastolic 100 mm Hg

Intervention : ACE inhibitors

Comparison : Diuretics

Outcome : prevent heart disease; stroke; end-organ damage?

“EBM” for therapy

1. Reports of individual studies

2. Reports of systematic reviews (‘RCT’)

5. Reports of qualitative study

3. Reports of Clinical Decision Analyses (CDA)

4. Reports of economic analyses

Integrative literature

Review article : * unsystematic

Systematic review : * in gathering, evaluating, presenting evidence * no formal statistical method

Meta-analysis : * systematic review + formal statistical analysis

Integrative literature

Review article

Systematic review

Meta-analysis


High rank of hierarchy of evidence (Randomized Controlled clinical trial / RCT)

Key elements of RCT

Randomization

Control Blinding


1. 1 Are the results of individual studies valid?

1. 2. Are the valid results of individual studies,important?

1. 3. Are the valid, important results of individual studies;

applicable to our patient?

1. 1. Are the results of individual studies, valid?

Primary guides:Primary guides:

1.1. 1. 1. Was the assignment of patients 1. 1. Was the assignment of patients to treatments randomized? to treatments randomized?

1.1. 1. 2. Was follow-up of patients sufficiently long1. 2. Was follow-up of patients sufficiently long and complete? and complete?

1.1. 1. 3. Were patients analyzed in the groups 1. 3. Were patients analyzed in the groups to which they were randomized? to which they were randomized?

• Preventing bias• Equal chance

• Balance of subjects characteristic

Toast / coinSimple randomization (random table)

Block randomization Stratified randomization

1.1.1. Was the assignment of patients to treatments randomized?

1.1. 2. Was follow-up of patients sufficiently long and complete?

Lost to follow up no more than 20%

JJournals like Evidence-Based Medicine and ACP Journal Club

won’t publish trials with > 80% follow-up.

1.1. 3. Were patients analyzed in the groups to which they were randomized?

““Intention to treat analysis”Intention to treat analysis”

All patients are analyzed in the groups to which they were initially assigned

A strategy for analyzing data in which all participants are included

in the group to which they were assigned, whether or not they completed

the intervention given to the group.

1. 1. Are the results of the study valid?

Secondary guides:Secondary guides:

1.1. 7. Was the randomization concealed? 1.1. 7. Was the randomization concealed?

1.1.1. 5. 1. 5. Aside from the experimental intervention,

were the groups treated equally?

1.1.1. 4. 1. 4. Were patients, health workers, and study personnel "blind" to treatment?

1.1. 1. 6. 1. 6. Were the groups similar at the start

of the trial?

1.1. 4. Patients, health workers, and study personnel "blind" to treatment?

Prevent biasPrevent bias

Single Single blindblind Double Double blind blind Triple blindTriple blind

Similar: Form Color Taste

Drug of administration

‘‘Blind’ interventionBlind’ intervention

SUBJECTS

EFFECT

EFFECT

CLINICAL TRIAL DESIGNS

TREATMENT GROUP

CONTROL GROUP

PARALLEL DESIGN TWO GROUPS :

“Wash-out Period”SUBJECTS

2. CROSS-OVER DESIGN :

TREATMENT A

TREATMENT B

EFFECT

EFFECT

TREATMENTB

TREATMENT A

EFFECT

EFFECT

1. 2. 1. What is magnitude of the treatment

effect?

1. 2. 2. How precise is the estimate

of the treatment effect?

1. 2. Are the valid results of individual study,

important?

1. 2. Elements of important of the treatment effect

p value, RRR, RRI, ARR, ARI, NNT, NNH

1. 2. 1. Magnitude of the treatment effect:

1. 2. 2. How precise is the treatment effect :

Confidence Interval (CI)

Study of statin to prevent stroke(5 years’ follow-up)

Stroke occurred among 5.7 % of patients randomized to control group (‘Control Event Rate = CER’) Stroke occurred among 4.3 % of patients randomized to experimental group

(‘Experimental Event Rate = EER’)

1.2. 1. Elements of magnitude of the treatment effect

RRR = {(CER – EER) / CER}

CER (study for preventing stroke) = 5.7%


RRR = {(CER – EER) / CER} RRR = (5.7% – 4.3%) / 5.7% = 25%

Statin therapy decreased the risk of stroke by 25% relative to those who receive placebo

EER (study for preventing stroke) = 4.3%


The situation in which the experimental treatment increase the risk of a good event as the ‘Relative Benefit Increase (RBI)’ or the risk of bad event as ‘Relative Risk Increase(RRI)

also can use the same formula (RRR):

RRR = RBI = RRI = {(CER – EER) / CER} RRR = RBI = RRI =(5.7% – 4.3%) / 5.7% = 25%

Relative Risk Reduction (RRR) :is the percent reduction in risk in treated group compared to the control group

The RRR is measure of how the treatment studied has reduced the frequency of an adverse event

1. 2. 1. Elements of magnitude of the treatment effect

Absolute Risk reduction (ARR):is the difference in risk between the control group and the treatment group


The situation in which the experimental treatment increase the risk of a good event as the ‘Absolute Benefit Increase (ABI)’ or the risk of bad event as ‘Absolute Risk Increase(ARI)

also can use the same formula (ARR):

ARR = ABI = ARI = (CER – EER) ARR = ABI = ARI =(5.7% – 4.3%) = 1.4%

Significance of Relative Risk ReductionSignificance of Relative Risk Reduction

Negative RRR (- 38%): treatment may do harm: patients given the new treatment might be 38% more likely to die than the control patients

RRR of 0%: no treatment effect or benefit

Positive RRR (50%): patients receiving the new treatment might have less than 1/2 risk of dying compared to not treated

The greater the relative risk reduction the more effective the therapy (>>> RRR efficacy of therapy)

1.2.1. Element of magnitude of the treatment effect

RRR = {(CER – EER) / CER}

CER : Control Event Rate (without treatment/placebo)

EER : Experimental Event Rate (with treatment)

Number Needed to Treat (NNT) :* Number of patients should be

treated to avoid 1 (one) bad outcome

* Number of patients should be treated

to have additional good outcome


Number Needed to Harm (NNH) : Number needed to harm 1 (one) patient from the therapy

Number Needed to Treat (NNT) = 1 / ARR* NNT = 1 / 1.4% = 72

we need to treat 72 people with a statin

(rather than placebo) for 5 years to prevent one additional person

from suffering a stroke


Therapy / treatment - case study

A randomized double blind control clinical trial on 3 month – 5 year old children with mild to

moderate croup (laryngotracheobronchitis). The experimental group : 2 mg (4 ml) nebulized budesonide.The control group : 4 ml nebulized normal saline.Event being prevented : hospital admission due to upper-airway obstruction.

27

N = 54

27

1

26

7

20

R

The study protocol

Hospitalized

Hospitalized

Non-Hospitalized

Non-Hospitalized

budesonide

normal saline

NoNo YeYess

Budesonide (E)Budesonide (E) 2626 11 2727NaCl (C)NaCl (C) 2020 77 2727

Upper-airway obstruction

X2 df =1 p = 0.04

Important

NoNo YeYess

Budesonide (E)Budesonide (E) 2626 11 2727NaCl (C)NaCl (C) 2020 77 2727

Upper-airway obstruction

CER = 7 / 27 = 0.26 ;

Important

Zain-Hamid, R; CMP, Faculty of Medicine, Universitas Suatera Utara.

EER = 1 / 27 = 0.04RRR = (CER – EER) / CERRRR = (0.26 – 0.04) / 0.26 = 85% ARR = (CER – EER) = (0.26 – 0.04) = 0.22 NNT = 1 / ARR = 1 / 0.22 = 5

Budesonide vs normal saline; Upper-airway obstruction

CERCER EEREER ARRARR NNTNNT

In the actual trialIn the actual trial 26% 4%4% 22%22% 55

In the hypothetical In the hypothetical trivial casetrivial case 0.000260.00026 0.000040.00004 0.000220.00022 50005000

Zain-Hamid, R; CMP, Faculty of Medicine, Universitas Suatera Utara.

Important

Confidence interval

1. 2. 2. Elements for deciding precision of the treatment effect

(<< CI precission of the treatment effect)

1. 3. 1. Is our patient so different from those Is our patient so different from those in the study that its results cannot in the study that its results cannot apply?apply?1. 3. 2. Is the treatment feasible in our setting?Is the treatment feasible in our setting?

1. 3. Are the valid, important results of this Are the valid, important results of this individual studies applicable to our patient?individual studies applicable to our patient?

1. 3. 3. What are our patient’s potential benefits What are our patient’s potential benefits and harms from the therapy?and harms from the therapy?

1. 3. 4. What are our patient’s values andWhat are our patient’s values and expectations for both the outcome expectations for both the outcome we are trying to preventwe are trying to prevent

and the treatment we are offering?and the treatment we are offering?

2. Reports of systematic reviews

2. 1. Are the results of this systematic review, valid?

2. 2. Is the valid evidence from this systematic review, important ?

2. 3. Are the valid, important results of this systematic review, applicable to ourpatient?

2. 1. Is the evidence from this systematic review, valid?

2. 1. 1. Is the systematic review 2. 1. 1. Is the systematic review of randomized trials? of randomized trials? 2. 1. 2. Does it describe a comprehensive and 2. 1. 2. Does it describe a comprehensive and detailed search for relevant trials? detailed search for relevant trials?

2. 1. 3. Were the individual studies assessed 2. 1. 3. Were the individual studies assessed for validity? for validity?

Primary Primary guide guide

Secondary guide Secondary guide 2. 1. 4. Were individual patient data 2. 1. 4. Were individual patient data (or aggregate data) used in analysis? (or aggregate data) used in analysis?

2. 2. Is the evidence from this systematic review, important?

2. 2. 1. Are the results consistent across studies? 2. 2. 1. Are the results consistent across studies?

2. 2. 2. What is the magnitude of treatment effect? 2. 2. 2. What is the magnitude of treatment effect?

2. 2. 3. How precise is the treatment effect? 2. 2. 3. How precise is the treatment effect?

2. 3. Are the valid, important results of this systematic review, applicable to our patient? 2. 3. 1. Is our patient so different from those 2. 3. 1. Is our patient so different from those in the study that is results cannot apply? in the study that is results cannot apply?

2. 3. 2. Is the treatment feasible in our setting? 2. 3. 2. Is the treatment feasible in our setting?

2. 3. 3. What are our patient’s potential benefits2. 3. 3. What are our patient’s potential benefits and harm from the therapy? and harm from the therapy?

2. 3. 4. What are our patient’s values and 2. 3. 4. What are our patient’s values and expectations for both the outcome expectations for both the outcome we are trying to prevent and we are trying to prevent and the adverse effects we may cause? the adverse effects we may cause?

3. 1. Are the results of this clinical decision analysis (CDA), valid?

3. 1. 1. Were all important therapeutic alternatives 3. 1. 1. Were all important therapeutic alternatives (including no treatment) & (including no treatment) & outcome included? outcome included?

3. 1. 2. Are the probabilities of the outcomes3. 1. 2. Are the probabilities of the outcomes valid & credible? valid & credible?

3. 1. 3. Are the utilities of the outcomes valid &3. 1. 3. Are the utilities of the outcomes valid & credible? credible?

3. 2. Are the valid results of this CDA, important?

3. 2. 1. Did one course of action lead 3. 2. 1. Did one course of action lead to clinically important gains? to clinically important gains?

3. 2. 2. Was the same course of action preferred3. 2. 2. Was the same course of action preferred despite clinically sensible changes despite clinically sensible changes in probabilities & utilities? in probabilities & utilities?

3. 3. Are the valid, important results of this CDA, applicable to our patient?

3. 3. 1. Do the probabilities in this CDA 3. 3. 1. Do the probabilities in this CDA apply to your patient? apply to your patient?

3. 3. 2. Can our patient state his/her utilities 3. 3. 2. Can our patient state his/her utilities in a stable, usable form? in a stable, usable form?

4. 1. Are the results of this economic analysis, valid?

4. 1. 1. Are well-defined courses of action 4. 1. 1. Are well-defined courses of action compared? compared?

4. 1. 2. Does it provide a specified view from 4. 1. 2. Does it provide a specified view from which the costs & consequences which the costs & consequences are being viewed? are being viewed?

4. 1. 3. Does it cite comprehensive evidence4. 1. 3. Does it cite comprehensive evidence on the efficacy of alternativeson the efficacy of alternatives

4. 1. Are the results of this economic analysis valid?

4. 1. 4. Does it identify all the costs &4. 1. 4. Does it identify all the costs & consequences we think it should & consequences we think it should & select credible & accurate measures select credible & accurate measures of them?of them?

4. 1. 5. Was the type of analysis appropriate4. 1. 5. Was the type of analysis appropriate for the question posed?for the question posed?

4. 2. Are the valid results of this economic analysis, important?

4. 2. 1. Are the resulting costs, 4. 2. 1. Are the resulting costs, or costs per unit of health gained, or costs per unit of health gained, clinically significant ? clinically significant ?

4. 2. 2. Did the results of this economic analysis 4. 2. 2. Did the results of this economic analysis change with sensible changes to costs &change with sensible changes to costs & effectiveness? effectiveness?

4. 3. Are the valid, important results of economic analysis applicable to our patient?

4. 3. 1. Do the costs in the economic analysis4. 3. 1. Do the costs in the economic analysis apply in our setting? apply in our setting?

4. 3. 2. Are the treatments likely 4. 3. 2. Are the treatments likely to be effective in our setting? to be effective in our setting?

ConclusionsConclusions Application of good therapy must be Application of good therapy must be

supported by EBM supported by EBM

Ability to appraise the results of many Ability to appraise the results of many kind of studies, reviews, analyes etc kind of studies, reviews, analyes etc

Arigatoo gozaimasu

Example: To express

results in a study

where

20 % of the treatment group (Y)

25 % of the control group (X) died

X-Y = 0.25 – 0.20 = 0.05Y / X = 0.20 / 0.25 = 0.80

1- (Y / X) x 100 = (1- 0.80) x 100 = 20 %

Elements of magnitude of the treatment effect

Absolute Risk Reduction (ARR or risk difference)

Relative risk (Ratio)

Relative Risk Reduction (RRR)

Interferon as secondary prevention Interferon as secondary prevention of multiple sclerosis (33 months of of multiple sclerosis (33 months of

treatment)treatment)

NNT 10 month = 9 x (33 / 10) NNT 10 month = 9 x (33 / 10) = 29.7= 29.7

Table 5.4 EBM-Sacket

NNT = (1 / ARR)NNT = (1 / ARR)

RRR = (CER-EER / CER) RRR = (CER-EER / CER)

ARR = (CER-EER)

(50% - 39%) / 50% = 22%(50% - 39%) / 50% = 22%

50% - 39% = 11 %

1 / 11% = 91 / 11% = 9

CER : 50 % & EER : 39 %CER : 50 % & EER : 39 %

Elements of magnitude of the treatment effect

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