Evidence-Based Journal Club: Intention-to-Treat, Odds and Risk. Paul D. Simmons, MD St. Mary’s Family Medicine Residency Program Grand Junction, Colorado

FPIN Clinical Inquiries: Reducing ACL Injuries in Female Athletes (p “Evidence-Based Answer: Neuromuscular training programs including plyometric and strengthening exercises significantly reduce noncontact ACL injuries in female soccer and handball players older than 14 years old.” Plyometrics: eccentric (lengthening) -> amortization (rest) -> concentric (explosive shortening). Goal is to improve speed-based power and neuromuscular control.

Intention-to-Treat Analysis “Investigators pooled data using an intention-to-treat analysis and found a reduction in the incidence of ACL injuries in trained athletes compared with untrained athletes…” What is an intention-to-treat analysis?

With which group should this cohort be analyzed? +Tx With which group should this cohort be analyzed? Treatment Group No Tx Randomization No Tx Control Group

+Tx Per protocol analysis: best if you want to know effects of treatment on a patient who WILL receive the treatment. Treatment Group Randomization No Tx No Tx Control Group

+Tx No Tx Intention-to-Treat Analysis: Best if you want to know the effects of a treatment on a population as a whole. Treatment Group Randomization No Tx Control Group

Per Protocol Intention-to-Treat Compares those who actually received the treatment to those who actually did not. Compares those who should have received treatment based on randomization to those who should not have received treatment. Very susceptible to bias: usually makes the treatment look better, more tolerable and more effective. Can be misused: Two surveys of RCTs in major medical journals found 50% used “intention-to-treat,” but not all used it correctly! For example: Exclusion of those who drop out of treatment because of adverse events, or have the studied outcome prior to treatment. For example: analysis of two groups who finished study, but misses those who dropped out or were lost to follow-up.

Odds and Other Ratios “Investigators pooled data using an intention-to-treat analysis and found a reduction in the incidence of ACL injuries in trained athletes compared with untrained athletes (0.85 versus 1.9 percent; odds ratio [OR] = 0.40; 95% confidence interval [CI], 0.27 to 0.60).” What?

What are the odds of throwing a four with a single die? a. 1 in 5 (1:5) b. 1 in 6 (1:6) Odds are the ratio of the likelihood of the event happening to the event not happening.

Odds ratio = (a:b)/(c:d) = ad/cb Outcome Yes No a b c d Yes Exposure/Treatment No The “odds ratio” is the ratio of the odds in one group to the odds in the other. Odds ratio = (a:b)/(c:d) = ad/cb

Plyometrics/Strengthening Odds Ratio ACL tears Note: If percentages are given (such as here), just set the treatment groups to 100 and do the math. Yes No 0.85 99.15 1.9 98.1 Yes Treatment group =100 Plyometrics/Strengthening No treatment group = 100 No The “odds ratio” is the ratio of the odds in one group to the odds in the other. Odds ratio = (0.85/99.15)/(1.9/98.1) = (0.85x98.1)/(1.9x99.15) = 83.39/188.39 = 0.44

Odds vs. Risk Usually, when odds and risks are approximately equal, OR ~ RR. Converting odds to risk: Risk = Odds / (1+Odds) Ex: Odds of rolling a four is 1:5, or 0.2. So, Risk = 0.2 / (0.2+1) = 0.2/1.2 = 0.167 or 16.7%.

Plyometrics/Strengthening Relative Risk ACL tears Yes No 0.85 99.15 1.9 98.1 Yes Plyometrics/Strengthening No The “relative risk” compares (1) those who had the outcome despite treatment to everyone who got the treatment versus (2) those who had the outcome despite no treatment to everyone who didn’t get treatment. RR = [a/(a+b)]/[c/(c+d)] = (0.85/100) / (1.9/100) = 0.0085/0.719 = 0.012

Relative Risk Reduction ACL tears Yes No 0.85 99.15 1.9 98.1 Yes Plyometrics/Strengthening No The “relative risk reduction” tells us how much the treatment reduces risk for those who received it compared to those who did not. RRR = 1-RR = 1- 0.012 = 0.988

Plyometrics/Strengthening Risk Difference ACL tears Yes No 0.85 99.15 1.9 98.1 Yes Plyometrics/Strengthening No “Risk difference” compares the risk in those who had the outcome with no treatment to those who had the outcome despite treatment. It’s a more intuitive number than RRR. RD = (c/c+d)-(a/a+b) = (1.9/100)-(0.85/100) = 0.019 - 0.0085 = 0.0105 or 1.05% lower risk in those who had the treatment.

Finally - Number Needed To Treat NNT converts Risk Difference into the number of patients who would have to receive the treatment for one outcome to be prevented. NNT = 100/(RD x 100%) NNT = 100/(0.0105 x 100%) NNT = 100%/1.05% NNT = 95 So, 95 female athletes over 14 years old would need to be treated with the study protocol exercises for one ACL tear to be prevented.

Take-Home Messages Intention-to-treat analyses minimize bias when the studies are about treatment effects. Make sure the analysis includes everyone randomized to either intervention, regardless of what actually happened. The odds are the likelihood of an event happening compared to it not happening (not happening vs. happening + not happening). The odds ratio compares the odds of an event happening to one group (say, the treatment group) to the odds of it happening in another group (the control group). Convert odds to risk by: odds / (odds + 1). Compare RR and RD: RR = [a/(a+b)] / [c/(c+d)] vs. RD = [c/(c+d)] - [a/(a+b)] NNT is always a useful, intuitive number: NNT = 100/(RD x 100%)