Absolute Risk Reduction, Number Needed to Treat, Back-of-the-Envelope Cost Effectiveness Analysis, Treatment Thresholds Revisited 10 November 2011 Michael A. Kohn, MD, MPP Using Randomized Trials to Quantify Treatment Effects (+ Natural experiments and instrumental variables – Tom Newman)

Problem-Writing Assignment Due in section next week (11/17/2011)! Include answers (Best if answers are separate, so we can try the question first without the answer.)

Diagnosis: Evaluate a test and then use it to determine whether a patient has a given disease. (Chs. 2, 3, 4, 5, 8) Treatment: Determine if a treatment is beneficial in patients with a given disease, and if so, whether the benefits outweigh the costs and risks. (Chs. 9, 10) In screening programs (Ch. 6), diagnosis and treatment are the most closely intertwined. Prognostic testing (Ch. 7) requires longitudinal studies and evaluation of calibration as well as discrimination. EBM is about using research studies to help in two related areas

Quantifying the Benefit of a Treatment: Take Home Points RCT Checklist Need baseline incidence of bad outcome*. Number Needed to Treat =NNT= 1/ARR Number Needed to (treat to) Harm = NNH = 1/ARI Back-of-the-envelope CEA: Treatment cost per bad outcome prevented = Treatment Cost x NNT *Unless the RR is 1 and RRR is 0.

RCT Checklist

Design and conduct Randomization to address issues of confounding Blinding of patients and clinicians to prevent differential co-interventions Blinding of outcome assessors to prevent bias Patient-Oriented Effect Measures (POEMs) vs. surrogate outcomes Decompose composite outcomes Good follow-up to eliminate differential losses to follow- up *For checklist on study validity, see Chapter 1B1 “Therapy”, in Guyatt and Rennie (eds.), Users Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice; AMA Press; RCT Checklist for Study Validity*

Analysis Intention-to-treat analysis (once randomized always analyzed) Compare entire randomization groups, not subgroups Between groups rather than within groups comparison *For checklist on study validity, see Chapter 1B1 “Therapy”, in Guyatt and Rennie (eds.), Users Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice; AMA Press; RCT Checklist for Study Validity*

RCTs (2 orthopedic, 3 CV, and 0 pediatric treatments) 1. Hip replacement versus screws for hip fractures in the elderly. 2. Immediate arthroscopy versus immobilization and PT in first shoulder dislocation. 3. ApoA-I Milano vs. placebo in acute coronary syndrome. 4. Aspirin versus placebo in suspected acute myocardial infarction: ISIS Intravascular gamma radiation vs. placebo to prevent re-blockage after cleaning out a blocked coronary artery bypass graft.

Randomization, Intention-to-Treat Analysis, and Follow-up: Hip Replacement vs. Screws Pt is an 81-year-old woman with a hip fracture Pt’s son is a physician. He asks about hip replacement vs. screws. Pubmed search  Parker MJ, Khan RJ, Crawford J, Pryor GA. Hemiarthroplasty versus internal fixation for displaced intracapsular hip fractures in the elderly. A randomised trial of 455 patients. J Bone Joint Surg Br. Nov 2002;84(8):

Displaced Femoral Neck Fracture = Hip Fracture

Internal Fixation = Screws

Hemiarthroplasty = Hip Replacement

Randomization, Intention-to-Treat Analysis, and Follow-up: Hip Replacement vs. Screws Randomized controlled trial of the effects of hip replacement vs. screws on re- operation and other outcomes in > 70- year-old patients with displaced, hip fractures. Parker MH et al. Bone Joint Surg Br. 84(8):

Randomization: Hip Replacement vs. Screws Why do a randomized experiment? Why not do an observational study comparing mortality, re-operation rates, etc. between patients who had hip replacements and patients who had screws? Parker MH et al. Bone Joint Surg Br. 84(8):

Intention-to-Treat: Hip Replacement vs. Screws Some patients randomized to the hip replacement group ended up getting screws. Why not include these patients’ outcomes in the screws group or at least exclude them from the hip replacement group? Parker MH et al. Bone Joint Surg Br. 84(8):

How to analyze those who were assigned to hip replacement but received screws?* Intention to Treat: Analyze in the hip replacement group (reduces effect size, bias towards the null) Per Protocol: Exclude from analysis (bias in favor of hip replacement) As Treated: Analyze in the screws group (bias in favor of hip replacment) *Generally they are older, weaker, or sicker than the rest of the group.

Losses to Follow-Up: Hip Replacement vs. Screws.* If each treatment group had 20% loss to follow-up, there could still be bias. What if those in the screws group were lost to follow-up because they got better and those in the hip replacement group were lost because they died? *In fact, there were no losses to follow-up in this study.

Patient Oriented Endpoints, Blinding: Arthroscopy versus Immobilization for 1st Shoulder Dislocation Pt is a 34-year-old man who dislocated his shoulder while surfing at Ocean Beach. He asks about early arthroscopic stabilization versus immobilization and PT. Pubmed search  Kirkley A, Griffin S, Richards C, Miniaci A, Mohtadi N. Prospective randomized clinical trial comparing the effectiveness of immediate arthroscopic stabilization versus immobilization and rehabilitation in first traumatic anterior dislocations of the shoulder. Arthroscopy. Jul-Aug 1999;15(5):

Outcomes Affected by Treatments* Dichotomous (e.g., recurrent dislocation) Continuous (e.g., Western Ontario Shoulder Disability Index {WOSI}) Endpoints Patient relevant (e.g., ability to return to sports) Surrogate (e.g., MRI findings) * Example: Arthroscopy vs. conservative tx for 1 st Anterior Shoulder Dislocation (Arthroscopy Jul-Aug;15(5): )

Blinding Blinding of Patients and Clinicians Eliminates differential co-interventions Blinding of Outcome Assessment Eliminates biased outcome assessment (including placebo effect)

Blinding Blinding less important when opportunity for cointerventions that affect outcomes is minimal, and outcome is not subjective. Hip Replacement vs Screws for hip fracture, with endpoints of mortality and re-operation: patients, clinicians, and outcome assessors not blinded. Arthroscopy vs. non-operative management of shoulder dislocation, with endpoints of re-dislocation, and WOSI*: patients not blinded, but clinicians and outcome assessors (therapists) were blinded. *Western Ontario Shoulder Disability Index

Between-groups Comparison: ApoA-I Milano vs. Placebo to Reduce Atheroma Volume in Acute Coronary Syndrome Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. Jama 2003;290(17):

Percent Atheroma Volume in the Target Coronary Segment NBaselineFollow-UpChangeP Value* Placebo ApoA-I Milano 15 mg/kg mg/kg Combined * P values for within-group comparison from Wilcoxon signed rank test. For between-group comparison, P = 0.29 Between-groups Comparison: ApoA-I Milano vs. Placebo to Reduce Atheroma Volume in Acute Coronary Syndrome

Sub-group Analysis: ISIS II* 30-day mortality *Lancet 1988;2(8607): OverallGeminis and Libras Other signs Aspirin9.4%11.1%9.0% Placebo11.8%10.2%12.1%

Sub-group Analysis: ISIS II* 30-day mortality *Lancet 1988;2(8607): AspirinPlacebo DiedTotal%DiedTotal% Gemini/Libra % % All other signs % %

Composite Endpoints: Irradiation to prevent re- blockage after cleaning out a blocked coronary artery bypass graft. Major Cardiac Event YesNo Bypass Graft Irradiation % Placebo % “At 12 months, … the rate of major cardiac events was 49 percent lower (32 percent vs. 63 percent, P<0.001). “ Waksman, R., A. E. Ajani, et al. (2002). "Intravascular gamma radiation for in- stent restenosis in saphenous-vein bypass grafts." N Engl J Med 346(16):

“Major Cardiac Event” = Death or MI or Revascularization Procedure Composite Endpoints: Irradiation to prevent re- blockage after cleaning out a blocked coronary artery bypass graft.

DEATH YesNo Bypass Graft Irradiation % Placebo % Waksman, R., A. E. Ajani, et al. (2002). "Intravascular gamma radiation for in- stent restenosis in saphenous-vein bypass grafts." N Engl J Med 346(16): Composite Endpoints: Irradiation to prevent re- blockage after cleaning out a blocked coronary artery bypass graft.

Death or MI YesNo Bypass Graft Irradiation5?54608% Placebo6?556010% Waksman, R., A. E. Ajani, et al. (2002). "Intravascular gamma radiation for in- stent restenosis in saphenous-vein bypass grafts." N Engl J Med 346(16): Composite Endpoints: Irradiation to prevent re- blockage after cleaning out a blocked coronary artery bypass graft. Can’t tell from paper.

DEATH or MI YesNo Bypass Graft Irradiation % Placebo060 0% Composite Endpoints: Irradiation to prevent re- blockage after cleaning out a blocked coronary artery bypass graft. Could have been… Mortality or MI worse but composite endpoint better.

*For checklist on study validity, see Chapter 1B1 “Therapy”, in Guyatt and Rennie (eds.), Users Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice; AMA Press; (Or try ) DONE: RCT Checklist for Study Validity* Randomization to address issues of confounding Blinding of patients and clinicians to prevent differential co-interventions Blinding of outcome assessors to prevent bias Patient-Oriented Effect Measures (POEMs) vs. surrogate outcomes Take care with composite outcomes Good follow-up to eliminate differential losses to follow- up Intention-to-treat analysis (once randomized always analyzed) Between groups rather than within groups comparison Compare entire randomization groups, not subgroups

RCTs 1. Hip replacement versus screws for hip fractures in the elderly. 2. Immediate arthroscopy versus immobilization and PT in first shoulder dislocation. 3. ApoA-I Milano vs. placebo in acute coronary syndrome. 4. Aspirin versus placebo in suspected acute myocardial infarction: ISIS Intravascular gamma radiation vs. placebo to prevent re-blockage after cleaning out a blocked coronary artery bypass graft.

Effect Size (Dichotomous Outcomes*) RR RRR ARR NNT ARI NNH * Not going to discuss continuous outcomes today

This study was properly randomized but not blinded, used an intention-to-treat analysis, and had NO losses to follow- up. Results follow… Hip Replacement vs. Screws

Reduced Re-operation Re-operationNo Re-operationRisk Hip Replacement /229 =5.2% Internal Fixation with Screws /226 =39.8% Risk Ratio (RR):5.2%/39.8% =0.13 Relative Risk Reduction (RRR):1 - RR =87% Absolute Risk Reduction (ARR):39.8% - 5.2% =34.6% Number Needed to Treat (NNT)1/ARR =3 (Need to treat 3 patients with hip replacement instead of screws to prevent one patient requiring re-operation.)

Measures of Treatment Effect RR= Risk Ratio = RR < 1 means treatment is beneficial RRR = Relative Risk Reduction = 1-RR Bad Outcome No Bad Outcome Totals Treatmentaba + b Controlcdc + d Totalsa + cb + dN = a + b + c + d

Beware of the Odds Ratio RR = Risk Ratio = (a/b) (a/c) OR = Odds Ratio = = = ad/bc (c/d) (b/d) Bad Outcome No Bad Outcome Totals Treatmentaba + b Controlcdc + d Totalsa + cb + dN = a + b + c + d In the hip replacement vs. screws example, the baseline risk of reoperation (with screws) is 40%, so the baseline odds are 67%. The risk (or odds) with replacement is about 5%, so RR ≈ 5/40 ≈ 1/8; but the OR ≈ 5/67 ≈ 1/13.

Beware of the Odds Ratio Major Cardiac Event YesNo Bypass Graft Irradiation % Placebo % Irradiation to prevent re-blockage after cleaning out a blocked coronary artery bypass graft. “ The risk of a major cardiac event was significantly lower in the iridium- 192 group than in the placebo group (odds ratio, 0.27; 95 percent confidence interval, 0.13 to 0.57; P<0.001) “ Waksman, R., A. E. Ajani, et al. (2002). "Intravascular gamma radiation for in- stent restenosis in saphenous-vein bypass grafts." N Engl J Med 346(16):

Beware of the Odds Ratio Major Cardiac Event YesNo Bypass Graft Irradiation % Placebo % Irradiation to prevent re-blockage after cleaning out a blocked coronary artery bypass graft. RR = (19/60)/(38/60) = 0.50 OR = (19/41)/(38/22) = 0.27

Measures of Treatment Effect ARR = Absolute Risk Reduction = c/(c+d) - a/(a+b) NNT = Number Needed to Treat (to prevent 1 bad outcome) = 1/ARR Bad Outcome No Bad Outcome Totals Treatmentaba + b Controlcdc + d Totalsa + cb + dN = a + b + c + d

Q: What does the 34% reduction mean?

Nimotop® Ad Graph 22% 33% RR = 21.8%/33% =.66 RRR = = 34% ARR = 33% % = 11.2%

Original figure 11% 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% To scale

Why is NNT = 1/ARR? 67 no stroke anyway 22 strokes with Nimotop® 11 strokes prevented 22 strokes with with treatment 33 strokes with no treatment 100 SAH patients treated

Why is NNT 1/ARR? Treat 100 SAH patients; prevent 11 strokes. 100/11 = 1/11% = 1/ARR = 9 patients treated per stroke prevented.

Number Needed to Treat … With what? To prevent what? In whom?

NNT Practice In patients < 30 years old with first-time acute anterior shoulder dislocation, prompt arthroscopic surgery (vs. standard conservative therapy) reduces the 2-year re- dislocation rate by almost 33% in absolute terms (from about 50% to about 17%).* How many first-time dislocation patients do we need to treat with arthroscopy to prevent one having re-dislocation at 2 years? *Kirkley A, et al. Arthroscopy. Jul-Aug 1999;15(5): Numbers rounded for purposes of exposition.

NNT Practice ISIS- 2*. Aspirin therapy (one month of 160 mg/day) in patients with acute myocardial infarction (AMI) reduced 30-day cardiovascular mortality from 11.8% in the placebo group to 9.3% in the aspirin group. *Lancet 1988;2(8607):

NNT Practice How many AMI patients do we need to treat with aspirin to prevent one CV death at 30 days? Death at 30 Days DiedLived Aspirin % Placebo % -2.5% *Lancet 1988;2(8607):

The risk ratio (RR) or relative risk reduction (RRR = 1-RR) associated with a treatment is of minimal use without knowing the baseline level of risk*. Problem with the Relative Risk Reduction *The RR is not completely useless without the baseline risk. If RR=1, the tx is useless regardless of the baseline risk. If RR > 1, the treatment is harmful. Also, if you already know the baseline risk in your own population, the RR may be all you need.

Irradiation to prevent re-blockage after cleaning out a blocked coronary artery bypass graft. “At 12 months, the rate of revascularization of the target lesion was 70 percent lower in the iridium-192 group than in the placebo group” Waksman, R., A. E. Ajani, et al. (2002). "Intravascular gamma radiation for in- stent restenosis in saphenous-vein bypass grafts." N Engl J Med 346(16): After cleaning out blocked bypass graft, how many do we have to treat with iridium to prevent one revascularization procedure (of the target lesion)? Problem with the Relative Risk Reduction

“At 12 months, the rate of revascularization of the target lesion was 70 percent lower in the iridium-192 group than in the placebo group” Waksman, R., A. E. Ajani, et al. (2002). "Intravascular gamma radiation for in- stent restenosis in saphenous-vein bypass grafts." N Engl J Med 346(16): After cleaning out blocked bypass graft, how many do we have to treat with iridium to prevent 1 revascularization procedure in the next 12 months? Problem with the Relative Risk Reduction The baseline risk (i.e., risk in the placebo group) was 57%

Baseline 12-month risk of revascularization = 57% RRR = 0.70 ARR = RRR × Risk control ARR = 0.70 × 0.57 = 0.40 NNT = 1/0.40 = 2.5 Need to treat 2.5 unclogged grafts with radiation to prevent 1 from needing revascularization of the target lesion in the next 12 months. Problem with the Relative Risk Reduction: Need Baseline Risk

ARR = RRR × Risk control

( 1 – RR ) × Risk control ARR = RRR × Risk control (1 – Risk treatment / Risk control ) × Risk control ( RRR ) × Risk control Risk control – Risk treatment ARR

Analysis and Presentation of Results Relative risk most relevant for assessing causation, more easily generalized Absolute risk reduction (ARR) most relevant for clinical decisions 1/(ARR) = Number Needed to Treat (NNT) per outcome prevented

Flu Prophylaxis? Pt is a 6-year-old girl with fever, myalgias, cough and sore throat X 1 day Should you rx prophylactic Tamiflu® for the pt’s mother who is pregnant? Pubmed search  Welliver R et al. Effectiveness of Oseltamivir in Preventing Influenza in Household Contacts: A Randomized Controlled Trial. JAMA 2001; 285:

Prophylactic Oseltamivir: Index Case Flu+* Household Contacts FluNo FluRisk Oseltamivir /209 =1.4% Placebo /206 =12.6% Risk Ratio (RR):1.4%/12.6% =0.11 Relative Risk Reduction (RRR):1 - RR =89% Absolute Risk Reduction (ARR):12.6% - 1.4% =11.2% Number Needed to Treat (NNT)???? *Welliver R et al. Effectiveness of Oseltamivir in Preventing Influenza in Household Contacts: A Randomized Controlled Trial. JAMA 2001; 285:

Prophylactic Oseltamivir: Index Case Flu+* Household Contacts FluNo FluRisk Oseltamivir /209 =1.4% Placebo /206 =12.6% Risk Ratio (RR):1.4%/12.6% =0.11 Relative Risk Reduction (RRR):1 - RR =0.89 Absolute Risk Reduction (ARR):12.6% - 1.4% =11.2% Number Needed to Treat (NNT)1/ARR =9 *Welliver R et al. Effectiveness of Oseltamivir in Preventing Influenza in Household Contacts: A Randomized Controlled Trial. JAMA 2001; 285:

Number Needed To Harm NauseaNo NauseaRisk Oseltamivir /494 =5.5% Placebo /461 =2.6% Risk Ratio (RR):5.5%/2.6% =2.1 Absolute Risk Increase (ARI):5.5% - 2.6% =2.9% Number Needed to Harm (NNH):1/ARI =35 NNH is really number needed to treat to cause one undesired effect.

Number Needed to Harm Not an apt term for number needed to treat to cause one bad outcome. Would prefer NNTc (“Number Needed to Treat to cause”) vs. NNTp (“Number Needed to Treat to prevent”), but NNH is well established.

Number Needed to Harm TransfusionNo Transfusion Hip Replacement /223 =19.7% Internal Fixation with Screws /223 =1.8% Risk Ratio (RR):19.7%/1.8% =11.00 Absolute Risk Increase (ARI):19.7% - 1.8% =17.9% Number Needed to Harm (NNH)????

Number Needed to Harm TransfusionNo Transfusion Hip Replacement /223 =19.7% Internal Fixation with Screws /223 =1.8% Risk Ratio (RR):19.7%/1.8% =11.00 Absolute Risk Increase (ARI):19.7% - 1.8% =17.9% Number Needed to Harm (NNH)1/ARI =6 (Need to treat 6 patients with hip replacement instead of screws to cause one patient to require transfusion.)

Ratio of Undesired to Desired Effects “Harms” / Bad Outcome Prevented = ARI/ARR = NNT/NNH

Ratio of Desired to Undesired Effects Harms Caused / Bad Outcome Prevented = ARI/ARR Hip Replacement vs. Screws for Hip Fx Risk Increase for transfusion: ∆ Risk Trx = 19.7% - 1.8% = 17.9% Risk Decrease for re-operation: ∆ Risk Re-Op = 39.8%-5.2% = 34.6% Transfusion Caused/Reoperation Prevented: 17.9/34.6 = 0.52 ≈ 1/2 Or 2 Reoperations Prevented Per Transfusion Caused

Ratio of Undesired to Desired Effects Cases of Nausea / Flu Case Prevented = 2.9%/ 11% = 0.25 =1/4 Or 4 Flu Cases Prevented per Case of Nausea caused

BOTE CEA Back-of-the-Envelope Cost Effectiveness Analysis (In book, this is referred to a “treatment cost per bad outcome prevented.”)

Back-of-the-Envelope Cost Effectiveness Analysis How many patients do I need to treat (at the treatment cost) to prevent 1 bad outcome? Number Needed to Treat (NNT) = 1/ARR Cost of preventing one bad outcome = NNT x Treatment Cost* *This is just ∆$Cost /∆Risk.

BOTE CEA: Oseltamivir Index Case Flu + NNT = 9 (Treat 9 household contacts, prevent 1 flu case) NNT x Treatment Cost* = 9 x $50 = $450/flu case prevented Cost of Tamiflu 75 mg #10 = $ /4/09www.drugstore.com

BOTE CEA: Aspirin after MI NNT = 1/0.025 = 40 (Treat 40 MI patients to prevent 1 death at 30 days) At Rite Aid, a bottle (#120) of 81 mg aspirin tablets costs $5.00, but you only need 60. NNT x Treatment Cost* = 40 x $2.50 = $100/death prevented Death at 30 Days DiedLived Aspirin % Placebo % -2.5% *Lancet 1988;2(8607):

BOTE CEA Example Letrozole (Femara®) to prevent breast cancer recurrence after 5 years of tamoxifen therapy.

Drug cuts risk of breast-cancer relapse Findings so promising, study halted so scientists could release news By Sabin Russell Chronicle Medical Writer Front Page, San Francisco Chronicle 10/10/03 RCT of Letrozole (Femara®), after tamoxifen, to prevent breast cancer recurrence

RRR or ARR? “The trial was interrupted almost 2½ years after it began. Researchers had scheduled a midpoint peak at the data, and found letrozole was apparently working far better than expected. The women who took it had 43 percent fewer recurrences of their breast cancer compared to those assigned in the study to take a placebo, or dummy pill.”

Femara Trial Results Recurrence No Recurrence Letrozole Placebo Risk(Letrozole) = 75/2575 = 2.9% Risk(Placebo) = 132/2582 = 5.1% RR = 2.9/5.1 = 0.57 RRR = = 43% N Engl J Med Nov 6;349(19):

Femara Trial Results ARR = 5.1% - 2.9% = 2.2% NNT = 1/2.2% = 45 Treatment Cost = $266/month* x 12 months/year x 2.5 years = $7980 Femara Cost per Recurrence Prevented = $7980 x 45 ≈ $360,000 *2.5mg tablets are available from $266/30 day supply (30 tablets) 1/7/2008.

BOTE CEA Examples Oseltamivir to prevent flu in household contacts of flu+ individuals: $450 per case of flu prevented Aspirin after acute MI: $100 per death prevented at 30 days Letrozole after tamoxifen to prevent recurrent breast cancer: $360,000 per recurrence prevented at 2.5 years

BOTE vs. “Real” CEA Estimates treatment costs per bad outcome prevented – including the bad outcome’s costs Treatment Costs Bad Outcome + Bad Outcome’s Costs “Real” Cost Effectiveness Analysis: Treatment Costs – Bad Outcome’s Costs Bad Outcome

BOTE vs. “Real” CEA Back of the envelope: Treatment Costs Bad Outcome + Bad Outcome’s Costs “Real”: Treatment Costs – Bad Outcome’s Costs Bad Outcome Note that “real” analysis LOWERS the cost per bad outcome prevented and makes treatment look better.

Quantifying the Benefit* of a Treatment: Take Home Points The Risk Ratio or Relative Risk Reduction associated with an intervention is of minimal use without a baseline incidence of bad outcomes. You need to have an absolute risk reduction to calculate number needed to treat. (NNT = 1/ARR) For undesired effects of treatment, calculate the absolute risk increase (ARI), and the number needed to harm (NNH = 1/ARI) Back-of-the-envelope CEA: Treatment cost per bad outcome prevented = Treatment Cost x NNT *With regard to dichotomous outcomes

RCTs 1. Hip replacement vs. screws for hip fracture 2. Arthroscopy vs. Immobilization for 1st time shoulder dislocation 3. ApoA-I Milano vs. Placebo to reduce atheroma volume after acute coronary syndrome 4. ISIS-II 5. Intravascular gamma radiation vs. placebo to prevent re-blockage after cleaning out a blocked coronary artery bypass graft. 6. Nimodopine vs. placebo to reduce cerebral infarction after subarachnoid hemorrhage. 7. Oseltamivir to prevent influenza in household contacts of patients with the flu 8. Letrozole (Femara®) vs. placebo to prevent breast cancer recurrence after 5 years of tamoxifen therapy.