Lecture 9: Analysis of intervention studies

• Randomized trial - categorical outcome

• Measures of risk:– incidence rate of an adverse event (death, etc)

• It = incidence rate in treatment group

• Ic = incidence rate in control group

• Example (mammography and mortality):• It = 2/10,000/year

• Ic = 4/10,000/year

Risk difference and ratio

Risk difference = Ic - It/units

– usually easier to express as risk reduction

– 4 - 2/10,000/year = 1/10,000/year

Risk ratio (relative risk) = Ic = 4/2 = 2.0

It

Alternatively: = It = 2/4 = 0.50

Ic

Relative risk reduction

• Analogous to attributable risk percent

• Sometimes called percent effectiveness

= risk difference = Ic - It

risk in control group Ic

= 2/4 = 50%

• Can be computed from the risk ratio: 1 - 1

RR

= 1 -1/2

Example from GUSTO trial

• tissue plasminogen activator (TPA) vs streptokinase (SK) as thrombolytic strategy in treatment of AMI.

30-day mortality in TPA group = 6.3%

• 30-day mortality in SK group = 7.3%

Measures of effect

RATE/RISK RATIO

SK rate = 7.3 = 1.16

TPA rate 6.3

RELATIVE RISK REDUCTION

SK rate – TPA rate = 7.3 – 6.3 = 14%

SK rate 7.3

[also calculated as 1 – (1/rate ratio)]

Measures of effect (cont)

ABSOLUTE RISK REDUCTION (rate/risk difference; attributable risk)

SK rate – TPA rate = 7.3% – 6.3% = 1.0%

NUMBER NEEDED TO TREAT (NNT)(Reciprocal of risk difference)

1 = 1 = 100

SK rate – TPA rate .01

SELECTION OF EFFECT MEASURES

Ratio measures assess strength of effect - how effective is the treatment?

Difference measures take into account frequency of the outcome – can assess whether it is worthwhile (allocation of time and $$)

Both ratio and difference measures are needed

All these measures are estimates and are subject to sampling error – need confidence intervals to determine their precision

All the measures are limited by the study(ies) that generated them – they may vary by patient characteristics, adherence to treatment, duration of follow-up, etc)

Measures consider only beneficial and not adverse effects of treatment.

Aspirin in prevention of MI among male smokers

(data from Physicians’ Health Study)

5-year incidence of MI:

aspirin group = 1.2%

placebo group = 2.2%

Risk ratio = 1.8

Relative risk reduction = 45%

Absolute risk reduction = 1.0% in 5 years

NNT = 100 for 5 years (to prevent 1 MI)

Antihypertensive treatment in 75-year old women with BP of 170/80

(data from SHEP study)

• 5-year incidence of stroke:

treatment group = 5.2%

placebo group = 8.2%– Risk ratio = 1.6– Relative risk reduction = 37%– Absolute risk reduction = 3.0% in 5 years– NNT = 33 / 5 years (to prevent 1 stroke)

Measures of effect in RCTs: continuous outcomes

• Example: RCT of antidepressant vs placebo:

• Measures on depression scale at baseline and at follow-up

• Possible measures:– Difference in mean scores at follow-up – Difference in change scores from baseline to

follow-up

Measures of effect in RCT: adjustment for covariates

• Is it necessary?

• Compare characteristics of study groups at baseline (statistical testing not appropriate but may be requested!)

• Regression models:

– time to event: Cox proportional hazards

– categorical outcome at point in time: multiple logistic regression

– continuous outcome (at point in time or change score): multiple linear regression

Measures of effect in observational studies

• Cohort studies:

– can use same measures as in RCTs but control of confounding is essential

• Case-control studies:

– odds ratio may be used to estimate relative risk under certain assumptions

– relative risk reduction can be computed as:

1 - 1/OR

– risk difference and NNT cannot normally be computed from case-control studies

Example: a quasi-randomized trial of a 2-stage ED intervention for seniors

• 2-stage intervention:– screening with ISAR screening tool

– (if ISAR 2+): brief, standardized nurse assessment

– referrals to primary MD, CLSC, etc, as needed

• Patients randomized by day of visit to:– intervention

– usual care

• Outcomes (4 months after ED visit):– Functional decline

Example: a quasi-randomized trial of a 2-stage ED intervention for seniors

• Outcomes (4 months after ED visit):– Functional decline

– Change in depresssive symptoms

– Caregiver physical and mental health

– Patient and caregiver satisfaction with care

• Which method of analysis?

Example: Systematic detection and multidisciplinary care of delirium in older

medical inpatients Cole et al, CMAJ 2002; 167:753-9

• Intervention group:– Consultation by geriatrician or psychogeriatrician

– Identification of associated factors - recommendations

– Nurse daily visits

• Control group:– Usual care

– Limitations?

Screened for delirium(n = 1855)

Prevalent delirium(n=243)

No prevalent delirium(n=1612)

Total delirium(n=299)

Incident delirium(n=56)

No incident delirium(n=56)

Refused(n=72)

Randomized(n=227)

Intervention(n=113)

Control(n=114)

Incidence rate = 3%

Prevalence rate = 13%

SCREENING AND ENROLLMENT

8 weeks post-discharge8 weeks post-dischargefollow-upfollow-up

Intervention(n=113)

Control(n=114)

In-hospital death 25% 22%

Withdrew before discharge 7% 2%

Still in hospital at 8 weeks 16% 13%

Discharged before 8 weeks 65% 77%

Died after discharge 4% 9%Refused follow-up 5% 7%Completed follow-up 56% 61%

PRIMARY OUTCOMEPRIMARY OUTCOME

MEASUREMEASURE Mini-Mental State Exam (MMSE):

Every 2-3 days during 1st week, then weekly until discharge

If discharged before 8 weeks: 8-week post discharge home assessment

PRIMARY OUTCOMEPRIMARY OUTCOME

MEASURE MEASURE (continued)(continued)

Time to improvement in hospital Improvement = MMSE score

persistently at least 2 points higher than initial score

Kaplan-Meier survival curves ofKaplan-Meier survival curves ofpercent with improved MMSE scorepercent with improved MMSE score

0

10

20

30

40

50

60

70

0 5 10 15 20 25 30 35 40

Days from enrollment

% improved

Intervention (n=109)

Control (n=109)

Kaplan-Meier survival curves of percent Kaplan-Meier survival curves of percent with improved MMSE scorewith improved MMSE score

stratified by dementiastratified by dementia

0

10

20

30

40

50

60

70

0 5 10 15 20 25 30 35 40

Days from enrollment

% improved

Intervention, no dementia (33)Control, no dementia (n=36)Intervention, with dementia (n=67Control, with dementia (n=64)

Measure of effect

• Hazard ratio (HR) for shorter time to improvement = 1.10 (95% CI: 0.74, 1.63)

• Pre-specified sub-group analyses:– no dementia: HR 1.54 (0.80, 2.97)– less comorbidity HR 1.36 (0.75, 2.46)

• Conclusion?