1 absolute risk reduction, number needed to treat, back-of-the-envelope cost effectiveness analysis,...
TRANSCRIPT
1
Absolute Risk Reduction, Number Needed to Treat, Back-of-the-Envelope Cost Effectiveness Analysis, Treatment Thresholds Revisited
1 November 2012Michael A. Kohn, MD, MPP
Using Randomized Trials to Quantify Treatment Effects
2
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
3
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.
4
RCT Checklist
5
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; 2002.
RCT Checklist for Study Validity*
6
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; 2002.
RCT Checklist for Study Validity*
7
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):1150-1155.
8
Displaced Femoral Neck Fracture = Hip Fracture
9Internal Fixation = Screws
10Hemiarthroplasty = Hip Replacement
11
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):1150-1155.
12
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):1150-1155.
13
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):1150-1155.
14
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.
15
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.
16
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):507-514
17
18
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 1st Anterior Shoulder Dislocation (Arthroscopy. 1999 Jul-Aug;15(5):507-14. )
19
Outcomes Affected by Treatments
Dichotomous (e.g. recurrent dislocation)
Continuous (e.g. WOSI)Endpoints Patient relevant (e.g., ability to
return to sports) Surrogate (e.g., MRI findings)
20
Blinding
Blinding of Patients and Clinicians Eliminates differential co-
interventions
Blinding of Outcome Assessment Eliminates biased outcome
assessment (including placebo effect)
21
BlindingBlinding 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
22
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):2292-2300.
23
Percent Atheroma Volume in the Target Coronary Segment
N Baseline Follow-Up Change P Value*
Placebo 11 34.8 34.9 0.1 0.97
ApoA-I Milano
15 mg/kg 21 39.7 38.4 -1.3 0.03
45 mg/kg 15 37.9 37.2 -0.7 0.45
Combined 36 39.0 37.9 -1.1 0.02
* 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
24
Sub-group Analysis: ISIS II*30-day mortality
*Lancet 1988;2(8607):349-360.
Overall Geminis and
Libras
Other signs
Aspirin 9.4% 11.1% 9.0%
Placebo
11.8% 10.2% 12.1%
25
Sub-group Analysis: ISIS II*30-day mortality
*Lancet 1988;2(8607):349-360.
Aspirin Placebo
Died Total % Died Total %
Gemini/Libra 150 1359 11.0% 147 1442 10.2%
All other signs 654 7228 9.0% 868 7157 12.1%
26
Composite Endpoints: Irradiation to prevent re-blockage after cleaning out a blocked coronary artery bypass graft.
Major Cardiac Event
Yes No
Bypass
Graft
Irradiation 19 41 60 32%
Placebo 38 22 60 63%“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): 1194-9.
27
“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.
28
DEATH
Yes No
Bypass Graft
Irradiation 4 56 60 6.7%
Placebo 4 56 60 6.7%
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): 1194-9.
Composite Endpoints: Irradiation to prevent re-blockage after cleaning out a blocked coronary artery bypass graft.
29
DEATH or MI
Yes No
Bypass Graft
Irradiation 5? 54 60 8%
Placebo 6? 55 60 10%
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): 1194-9.
Composite Endpoints: Irradiation to prevent re-blockage after cleaning out a blocked coronary artery bypass graft.
Can’t tell from paper.
30
DEATH or MI
Yes No
Bypass Graft
Irradiation 6 54 60 10%
Placebo 0 60 60 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.
31
*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; 2002. (Or try http://www.cche.net/usersguides/therapy.asp#Valid )
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
32
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-2.
5. Intravascular gamma radiation vs. placebo to prevent re-blockage after cleaning out a blocked coronary artery bypass graft.
33
Effect Size(Dichotomous Outcomes*)
RRRRRARRNNTARINNH
* Not going to discuss continuous outcomes today
34
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
35
Reduced Re-operation
Re-operation No Re-operation Risk
Hip Replacement 12 217 229 12/229 = 5.2%
Internal Fixation with Screws 90 136 226 90/226 = 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.)
36
Measures of Treatment Effect
RR= Risk Ratio =
RR < 1 means treatment is beneficial
RRR = Relative Risk Reduction = 1-RR
)/(
)/(
dcc
baa
Bad Outcome
No Bad Outcome
Totals
Treatment a b a + b
Control c d c + d
Totals a + c b + d N = a + b + c + d
37
Beware of the Odds Ratio
RR = Risk Ratio =
(a/b) (a/c)
OR = Odds Ratio = ------- = -------- = ad/bc
(c/d) (b/d)
)/(
)/(
dcc
baa
Bad Outcome
No Bad Outcome
Totals
Treatment a b a + b
Control c d c + d
Totals a + c b + d N = 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.
38
Beware of the Odds Ratio
Major Cardiac Event
Yes No
Bypass Graft
Irradiation 19 41 60 32%
Placebo 38 22 60 63%
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): 1194-9.
39
Beware of the Odds Ratio
Major Cardiac Event
Yes No
Bypass Graft
Irradiation 19 41 60 32%
Placebo 38 22 60 63%
Irradiation to prevent re-blockage after cleaning out a blocked coronary artery bypass graft.
RR = (19/60)/(38/60) = 0.50OR = (19/41)/(38/22) = 0.27
40
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
Treatment a b a + b
Control c d c + d
Totals a + c b + d N = a + b + c + d
41Q: What does the 34% reduction mean?
42
Nimotop® Ad Graph
22% 33%
RR = 21.8%/33% = .66 RRR = 1-0.66 = 34% ARR = 33% - 21.8% = 11.2%
43
Original figure
11%
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
To scale
44
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
45
Why is NNT 1/ARR?
Treat 100 SAH patients; prevent 11 strokes.
100/11 = 1/11% = 1/ARR = 9 patients treated per stroke prevented.
46
Number Needed to Treat …
With what? To prevent what? In whom?
47
NNT PracticeIn 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):507-514. Numbers rounded for purposes of exposition.
48
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):349-360.
49
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
Died Lived
Aspirin 804 7783 8587 9.3%
Placebo 1016 7584 8600 11.8%
-2.5%
*Lancet 1988;2(8607):349-360.
50
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, then the treatment is beneficial; 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.
51
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): 1194-9.
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
52
“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): 1194-9.
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%
53
Baseline 12-month risk of revascularization = 57%
RRR = 0.70ARR = RRR × Riskcontrol
ARR = 0.70 × 0.57 = 0.40NNT = 1/0.40 = 2.5Need 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
54
ARR = RRR × Riskcontrol
55
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
56
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; 285:748-754.
57
Prophylactic Oseltamivir: Index Case Flu+*
Household Contacts
Flu No Flu Risk
Oseltamivir 3 206 209 3/209 = 1.4%
Placebo 26 180 206 26/206 = 12.6%
29 386 415
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; 285:748-754.
58
Prophylactic Oseltamivir: Index Case Flu+*
Household Contacts
Flu No Flu Risk
Oseltamivir 3 206 209 3/209 = 1.4%
Placebo 26 180 206 26/206 = 12.6%
29 386 415
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; 285:748-754.
59
Number Needed To HarmNausea No Nausea Risk
Oseltamivir 27 467 494 27/494 = 5.5%
Placebo 12 449 461 12/461 = 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.
60
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.
61
Number Needed to HarmTransfusion No Transfusion
Hip Replacement 44 179 223 44/223 = 19.7%
Internal Fixation with Screws 4 219 223 4/223 = 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) ????
62
Number Needed to HarmTransfusion No Transfusion
Hip Replacement 44 179 223 44/223 = 19.7%
Internal Fixation with Screws 4 219 223 4/223 = 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 requiring transfusion.)
63
Ratio of Undesired to Desired Effects
“Harms” / Bad Outcome Prevented =ARI/ARR =NNT/NNH OrBad Outcomes Prevented / Harm Caused
= ARR/ARI =NNH/NNT
64
Ratio of Desired to Undesired Effects
Harms Caused / Bad Outcome Prevented = ARI/ARR = NNT/NNH*Hip Replacement vs. Screws for Hip FxRisk Difference for re-operation:
∆ Risk Re-Op = 5.2% - 39.8% = -34.6%
Risk Difference for transfusion: ∆ Risk Trx = 19.7% - 1.8% = +17.9%
Transfusion Caused/Reoperation Prevented: 17.9/-34.6 = -0.52 ≈ -1/2
*Easier here to divide ∆ transfusion by ∆ re-operation, rather than use NNH or NNT.
65
Ratio of Desired to Undesired Effects
Bad Outcomes Prevented / Harm Caused = ARR/ARI = NNH/NNT*Hip Replacement vs. Screws for Hip FxRisk Difference for re-operation:
∆ Risk Re-Op = 5.2% - 39.8% = -34.6%
Risk Difference for transfusion: ∆ Risk Trx = 19.7% - 1.8% = +17.9%
Re-operations prevented/Transfusion Caused: -34.6/17.9 = -1.93 ≈ -2
*Easier here to divide ∆ re-operation by ∆ transfusion, rather than use NNH or NNT.
66
Ratio of Undesired to Desired Effects
Cases of Nausea / Flu Case Prevented =
2.9%/ 11% = 0.25 OrFlu Cases Prevented / Nausea
Caused = 11%/2.9% = 4
67
BOTE CEA
Back-of-the-Envelope Cost Effectiveness Analysis
(In book, this is referred to a “treatment cost per bad outcome prevented.)
68
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 .
69
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 = $92.99 www.drugstore.com 11/4/09
70
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
Died Lived
Aspirin 804 7783 8587 9.3%
Placebo 1016 7584 8600 11.8%
-2.5%
*Lancet 1988;2(8607):349-360.
71
BOTE CEA Example
Letrozole (Femara®) to prevent breast cancer recurrence after 5 years of tamoxifen therapy.
72
Drug cuts risk of breast-cancer relapse
Findings so promising, study halted so scientists could release news
By Sabin RussellChronicle Medical Writer
Front Page, San Francisco Chronicle 10/10/03
RCT of Letrozole (Femara®), after tamoxifen, to prevent breast cancer recurrence
73
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.”
74
Femara Trial Results
RecurrenceNo
Recurrence
Letrozole 75 2500 2575
Placebo 132 2450 2582
Risk(Letrozole) = 75/2575 = 2.9%Risk(Placebo) = 132/2582 = 5.1%RR = 2.9/5.1 = 0.57RRR = 1- 0.57 = 43%
N Engl J Med. 2003 Nov 6;349(19):1793-802.
75
Femara Trial Results
ARR = 5.1% - 2.9% = 2.2%NNT = 1/2.2% = 45Treatment Cost = $266/month* x 12
months/year x 2.5 years = $7980Femara Cost per Recurrence Prevented =
$7980 x 45 ≈ $360,000
*2.5mg tablets are available from www.drugstore.com $266/30 day supply (30 tablets) 1/7/2008.
76
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
77
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
78
BOTE vs. “Real” CEABack 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.
79
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
80
RCTs
1. Hip replacement vs. screws for hip fracture 2. Arthroscopy vs. Immobilization for 1st time shoulder dislocation3. ApoA-I Milano vs. Placebo to reduce atheroma volume after
acute coronary syndrome4. ISIS-II5. 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 infaction 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.
81
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?
What if the 6-year-old doesn’t have the flu?
The relative risk reduction is the same (89%), but the baseline risk for the mother is so low that prophylactic oseltamivir doesn’t do much. (ARR is negligible, NNT is enormous.)
82
Prophylactic oseltamivir works if the index case has the flu, but you don’t know whether she does. You know that 45% of similar patients have laboratory proven influenza.
Probability of Flu + = 45%
83
NNT is calculated for patients with a particular condition “D”.
P = probability of that condition “D” in your patients
Your NNT* = NNT / P
Note that NNT* goes up as P = probability of condition “D” goes down.
Patient May Not Have The Condition That You’re Treating
*Assumes that treatment for patients without condition D has no value. (For D- patients, ARR = 0, NNT = ∞)
84
NNT if index case flu + = 9.Probability of flu = 0.45
NNT* = 9 / 0.45 = 20
Probability of Flu + = 45%
*Assumes that treatment when index case is flu - has no value (ARR = 0, NNT = ∞)
85
No Adjustment of NNH for Disease Prevalence
Oseltamivir is no less likely to cause nausea in household contacts of Flu- patients than in those of Flu+ patients.
Prevalence of Flu+ = P = 45%ARI for nausea is still: 5.5% - 2.6% = 2.9%But, ARR is now:
0.45(12.6 %-1.4%) = 5%
Cases of nausea caused for each case of flu prevented:2.6%/5% ≈ 1/2
86
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
45% Prob Flu+• NNT* = 9/0.45 = 20• NNT* x Treatment Cost = 20 x $50 = $1000/flu
case prevented
•Cost of Tamiflu 75 mg #10 = $92.99 www.drugstore.com 11/4/09
87
Treatment Threshold Probability from Cost-Effectiveness Threshold
IF you can specify the amount you are willing to spend on prophylactic oseltamivir to prevent one case of the flu, you can calculate the treatment threshold probability Ptt
88
Treatment Threshold Probability from Threshold Cost Effectiveness Ratio
Assume it is worth $2250 in oseltamivir to prevent one case of the flu. We can calculate the treatment threshold probability PTT:
NNT* x $50 = $2250NNT/ PTT = $2250/$50 = 45
NNT/45 = PTT
9/45= 0.2 = PTT
89
Review: Testing Thresholds (Chapter 3)
Probability of Disease
Treat none; no test
Treat based on test results
Treat all; no test
No Treat-Test Threshold
Test-Treat Threshold
Treatment Threshold
90
Calculate Test-Treat Threshold
Rapid Antigen Detection Test Sensitivity = 0.5 Specificity = 1.0 PTT =0.2 Ignore cost of test (Imperfect
but costless)
91
Cost-Effectiveness Threshold Example
Willing to spend $2250 on prophylactic oseltamivir per case prevented.
Ptt = $50/(11.2%×$2250) = 0.20
Using the Chapter 3 notation:C = $50B = (11.2% × $2250) - $50 = $200C/(C+B) = 50/(200+50) = 0.20
92
Estimating B (using only treatment costs)
V = Value of preventing ONE case (“worth $2250 in oseltamivir to prevent one flu case”)
C = Cost of treating one D- individual unnecessarily (household contact of a Flu- individual) ($50)
B = Cost of failing to treat one D+ individual (household contact of a Flu+ individual)
B = ARR × V – C
93
V = $2250 (worth $2250 in oseltamivir to prevent one case of the flu)
C = $50 (cost of txing one pt with oseltamivir)
ARR = 11.2% B = 11.2% x $2250 - $50 = $200
Estimating B (using only treatment costs)
94
Treatment Threshold Probability from B and C
C = $50B = $200B/C = 1:4 = Threshold OddsB/(B+C) = 1/5 = Threshold Prob =
PTT
95
Assumptions
Only considers drug/treatment costs, not side effects of treatment
Treatment does not reduce outcome risk among D- patients
Can specify the amount willing to spend in treatment costs to prevent one outcome