1. Number Needed to Treat Alex Djuricich, MD Indiana University School of Medicine Department of Medicine Ambulatory Rotation 2006-2007

2. Objectives To learn basic information used in evaluating articles about therapy To learn definitions of the following and be able to apply them to appraising articles on therapy: CER (Control event rate) EER (Experimental event rate) RRR (Relative risk reduction) ARR (Absolute risk reduction) NNT (Number Needed to Treat)

3. Objectives To learn the “correlaries” to each of these definitions for harm RRI (Relative risk increase) ARI (Absolute risk increase) NNH (Number needed to harm)

4. Hypothetical trial Trial of 1000 patients to compare use of MiGone (I made that one up? Like the name? Get it?) vs. placebo to prevent MI, given over 5 years. Patients for study are all healthy gym rats, coming from Bally’s Gym.

5. Trial stats Total number of patients N=1000 Control group N=400 MiGone group N=600 # who developed an MI 2018 # who developed myalgias 412

6. For MI CER 20/400 = 0.05, or 5% EER 18/600 = 0.03, or 3% ARR 0.05 – 0.03 = 0.02, or 2% RRR (0.05 – 0.03)/0.05 = 0.02/0.05 = 40%

7. For MI NNT 1/ARR 1/0.02 = 50 50 patients would need to be treated to prevent one MI in 5 years in Bally’s Gym patients

8. For myalgias CER 4/400 = 0.01, or 1% EER 12/600 = 0.02, or 2% ARI 0.02 – 0.01 = 0.01, or 1% RRI 0.02 – 0.01/0.01 = 0.01/0.01 = 1, or 100%

9. For myalgias NNH 1/ARI 1/0.01 = 100 100 patients would need to be treated with MiGone over 5 years to cause one case (harm) of myalgias

10. Case #1 You just completed your GI rotation, and are now doing Wishard wards. You admit a 50 year old alcoholic gentleman for abdominal pain. After imaging, you find that he has radiologic “cirrhosis” with evidence of portal hypertension. He has NEVER had an upper GI bleed

11. Case #1 continued You discuss preventive pharmacologic treatments in rounds with the attending In patient with cirrhosis and portal hypertension, does a non-selective beta blocker prevent gastroesophageal varices? Yes No

12. Article Beta-blockers to prevent gastroeophageal varices in patients with cirrhosis Groszmann RJ, et al. New Engl J Med 2005;353:2254-61.

13. Focus on Table #2 Total number of patients N=213 Control group N=105 Timolol group N=108 # who developed varices (%) 42 (40%)42 (39%) # who developed “Serious event” (buried on p.2258) 6 (5.7%)20 (18.5%)

14. Control Event Rate Percentage of those controls who develop the unwanted condition In our example, varices or complication from it 42/105 40%

15. Experimental Event Rate Percent of those in treatment group that developed the condition (varices) 42/108 38.9%

16. Absolute Risk Reduction The true reduction in risk between control patients and treated patients Difference between the CER and the EER CER – EER 0.4 – 0.389 0.011, or 1.1% That’s ok, but not very impressive!

17. Relative Risk Reduction (CER – EER)/CER (0.4 – 0.389)/0.4 0.011/0.4 0.0275, or 2.75% Remember, 2.75% sounds better than 1.1%, but it still isn’t very “good”

18. Number Needed to Treat (NNT) Meaningful way of expressing benefit of an active treatment over a control Defines treatment-specific event of an intervention

19. NNT Expression of the # of patients one would need to treat to prevent 1 additional adverse outcome (MI) or attain one additional benefit 1/ARR 1/0.011 91 (that is, 91 patients would need to be treated with timolol to prevent one additional case of varices) Impressive? Not impressive?

20. NNT Function of 4 elements ConditionCirrhosis pts InterventionTimolol vs. placebo Events being preventedVarices Duration of follow-up55 months Remember “DICE”

21. NNT Tells us in more concrete terms how much effort clinicians must expend to prevent one event, thus allowing comparisons with the amounts of efforts that must be expended to prevent the same or other events in patients with disorders

22. NNT Is a “good” NNT a low or a high number? The lower the NNT, the larger the magnitude of treatment effect

23. What about the “serious adverse events”? Need to remember that medications have side effects, and that one can calculate how often we “harm” someone by giving a medication designed to help. This “harm” is the side effect

24. CER For harm, the CER is still the same as before. However, it applies to the harm instead of the “good” effect In the example, it refers to “serious adverse events” (such as bradycardia)

25. EER This is really the same as before, except it applies to the rate for harm instead of for benefit In our example, the EER is for “serious adverse events”

26. ARI for “Harm” Absolute Risk Increase EER – CER Note NOT “CER – EER”

27. RRI Relative Risk Increase (EER – CER)/CER Remember, its always the Control that goes in the denominator

28. What about NNH? In general, a decision to use therapy involves risk vs. benefit Most therapies have side effects Same concepts for NNT apply to side effects. We call that number the NNH (number needed to harm)

29. NNH The number of patients who, if they received the experimental treatment, would lead to one additional patient being “harmed”, compared with patients who received the comparison treatment. 1/ARI

30. Table #2 Again Total number of patients N=213 Control group N=105 Timolol group N=108 # who developed varices (%) 42 (40%)42 (39%) # who developed “Serious event” (buried on p.2258) 6 (5.7%)20 (18.5%)

31. Let’s calculate for “serious adverse events” CER 6/105 (5.7%) EER 20/108 (18.5%)

32. For “adverse events” ARI 18.5% - 5.7% = 12.8%, or 0.128 RRI (18.5% - 5.7%) / 5.7%= 224.5%, or 2.245 NNH 1/ARI 1/0.128 7.8 (rounds to 8) patients need to be treated with timolol to cause one case of “serious adverse events” This is unfortunately not a very good number; we want a very high NNH (as opposed to NNT)

33. Case Take Home According to this one study, the numbers are not impressive enough to recommend timolol to PREVENT varices in patients with diagnosed cirrhosis. Remember that this is different from patients who have ALREADY had an upper GI bleed from varices secondary to cirrhosis. Those patients should get a beta blocker.

34. Questions?

35. Case #2 You admit a patient on University Wards at night for bacterial meningitis. The ER doctor calls you with results of the CSF showing a WBC count of 1024, after noting cloudy CSF from the tap. She wants to know which antibiotic you would like to use; need an answer in 1 minute; meningitis is a true medical emergency!! You recall from your pediatrics rotation about giving steroids in addition to antibiotics. In patients with bacterial meningitis, does the use of concomitant dexamethasone improve neurological outcome?

36. Example NEJM paper Dexamethasone in adults with bacterial meningitis deGans J, vandeBeek D, et al. New Engl J Med 2002;347:1549-56. Total patients: 301 patients 157 in dexamethasone (experimental) group 144 in placebo (control) group

37. NNT: Function of 4 elements 1. Condition meningitis 2. Intervention dexamethasone vs. placebo. Keep in mind that other treatments (antibiotics) were given to both groups, so placebo isn’t really “nothing” 3. Events being prevented unfavorable outcome (they define it), death 4. Duration of follow-up 8 weeks

38. Dexamethasone paper Total # of patients N=301 Control group N=144 Dexamethasone group N=157 Unfavorable outcome 3623 Death2111

39. Dexamethasone paper CER for unfavorable outcome 36/144 0.25, or 25% CER for death 21/144 0.25, or 15%

40. Dexamethasone paper EER for unfavorable outcome 23/157 0.15, or 15% EER for death 11/157 0.07, or 7%

41. Dexamethasone paper ARR for unfavorable outcome CER – EER 0.25 – 0.15 0.10, or 10% ARR for death CER – EER 0.15 – 0.07 0.08, or 8%

42. Dexamethasone paper NNT for unfavorable outcome 1/ARR 1/0.10 10. You would need to treat 10 meningitis patients with dexamethasone to prevent one patient getting an “unfavorable outcome” after 8 weeks NNT for death 1/ARR 1/0.08 12.5 (rounds up to 13). You would need to treat 13 meningitis patients with dexamethasone to prevent one death after 8 weeks

43. Dexamethasone How about NNH? Calculate it for each of the “side effects” you are interested in.

44. Dexamethasone paper Total # of patients Control group N=144 Dexamethasone group N=157 Hyperglycemia3750 Fungal infection48

45. Dexamethasone paper CER for hyperglycemia 37/144 0.26, or 26% CER for fungal infection 4/144 0.03, or 3%

46. Dexamethasone paper EER for hyperglycemia 50/157 0.32, or 32% EER for fungal infection 8/157 0.05, or 5%

47. Dexamethasone paper ARI for hyperglycemia EER – CER 0.32 – 0.26 0.06, or 6% ARI for fungal infection EER – CER 0.05 – 0.03 0.02, or 2%

48. Dexamethasone paper NNH for hyperglycemia 1/ARI for hyperglycemia 1/0.06 16.7 (rounds to 17) You would need to treat 17 patients with bacterial meningitis to cause one case of hyperglycemia over 8 weeks

49. Dexamethasone paper NNH for fungal infection 1/ARI for fungal infection 1/0.02 50 You would need to treat 50 patients with meningitis with dexamethasone to cause one case of fungal infection over 8 weeks

50. Case Take Home Consider steroids at the time of diagnosis of suspected meningitis. They clearly have a role in improving outcomes, but this comes at a cost of increased fungal infection Is it worth the risk? That is the “art” of medicine.

51. Summary CER (control event rate) EER (experimental event rate) ARR (absolute risk reduction) and ARI RRR (relative risk reduction) and RRI NNT (number needed to treat) NNH (number needed to harm)

52. Summary NNT: Expression of # of patients one would need to treat to prevent one additional adverse outcome or attain one additional benefit NNT is a function of: Condition Intervention Events being prevented Duration of follow-up Remember, “DICE”