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: 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 rate6.3 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-discharge follow-up

PRIMARY OUTCOME MEASURE Mini-Mental State Exam (MMSE):  Every 2-3 days during 1 st week, then weekly until discharge  If discharged before 8 weeks: 8-week post discharge home assessment

PRIMARY OUTCOME MEASURE (continued) Time to improvement in hospital  Improvement = MMSE score persistently at least 2 points higher than initial score

Kaplan-Meier survival curves of percent with improved MMSE score

Kaplan-Meier survival curves of percent with improved MMSE score stratified by dementia

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?