Transcript Applied Interpretation of Clinical Studies

Applied Interpretation
of Clinical Studies
Jim Hoehns, Pharm.D., BCPS, FCCP
Why is this Lecture
Important?

To make informed drug therapy decisions
we….
– Need to understand size of treatment effect
– Need to relate drug information accurately

Patient and physician perception of drug
therapy effect influences subsequent
behaviors and actions
Ann Intern Med 2007;146:848-56.
Let’s Talk About “Risk”…
Description
Aspirin prophylaxis in 50 y.o. men
Fatality risk per
100,000 person-years
10.4
Clozapine for schizophrenia
Rofecoxib (Vioxx) for arthritis pain
Passenger in car
Driving motorcycle
Firefighter
Semi-truck driver
Rock climbing
Cohen JT. Health Aff 2007;25:636-46.
35
76
11
450
10.6
44.8
36
Outline
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Absolute risk
Absolute risk reduction (ARR)
Relative risk (RR)
Relative risk reduction (RRR)
Odds ratio (OR)
Hazard ratio (HR)
Number needed to treat (NNT)
Number need to treat to harm (NNT:H)
– aka NNH

Confidence intervals (CI)
Taking the right “STEPS” when
evaluating new information
S = Safety
T = Tolerability
“Pooled drop-out rates”
E = Effectiveness -- Studies showing
that the new drug is better than
your current choice
P = Price
S = Simplicity of use
Allen Shaughnessey, Pharm.D.
Point Estimation

Definition: A “point estimate” is a
one-number summary of data
– If you had just one number to summarize
the inference from your study…
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Examples:
– Safety and efficacy trials: response rate,
median survivals
– Comparative trials: odds ratio, hazard
ratio
Elizabeth S. Garrett, Ph.D.
Which Looks Better?
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Lipitor 80mg/d (vs. Lipitor 10mg/d)
lowered the risk of MI and stroke by
22%
Lipitor 80mg/d (vs. Lipitor 10mg/d)
lowered the risk of MI and stroke by
2.2%
Absolute Risk &
Absolute Risk Reduction
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Risk is the probability or frequency of an
outcome
Migraine medication (6 mon.)
– Placebo: 30% recurrence
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Control event rate (CER)
– Drug M: 5% recurrence
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Experimental event rate (EER)
Absolute risk reduction (ARR)
– CER – EER = ARR
– 30% - 5% = 25%
Absolute Risk Reduction
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Helps discriminate huge treatment
effects from small ones
– Preserves information on the baseline risk
– Clinically meaningful information
Relative Risk and Relative
Risk Reduction
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Relative Risk - risk in treatment group relative to
that in control group
–
–
–
–
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Ratio of two incidence rates
EER/CER = RR
.05/.30 = 0.17
Appropriate for trials; not appropriate for case-control
studies
Relative risk reduction
– Expression of reduction in relative risk
– 1 – RR = RRR (1 - 0.17 = 0.83 or 83% RRR)
– RRR does not tell about size of effect on an absolute
scale
Relative Risk
Risk of the outcome if the risk factor is present
Relative Risk =
Risk of the outcome if the risk factor is absent
Example:
Breast CA No Breast CA
Estrogen Tx:
a = 80
b = 920
No Estrogen Tx:
c = 10
d = 990
a
a+b
Relative Risk =
=8
c
c+d
Measures risk of developing condition over a specified time
Odds Ratio
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Retrospective study (classically)
A method of representing probability
Estimates the odds of having the RF if the condition
is present divided by the odds of having the RF if
the condition is not present
– OR > 1: increased risk of group 1 to 2
– OR = 1: no difference in risk of group 1 compared to
group 2
– OR < 1: lower risk “protective” in risk of group 1
compared to group 2
Odds Ratio
Odds of being on HRT if Breast CA present
Odds Ratio =
Odds of being on HRT if Breast CA not present
Example:
Estrogen Tx:
Breast CA No Breast CA
a = 80
b = 920
OR = a / c = 8.6
b/d
No Estrogen Tx:
c = 10
d = 990
Ross et al.
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Case-control study in Los Angeles
– 1897 cases with incident breast CA
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1637 controls
– matched on age, race-ethnicity,
neighborhood
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All patients: no hysterectomy
Adjusted for breast CA risks
– e.g. age at menopause, age at menarche,
family Hx, nulliparity, body weight, etc.
Ross et al. JNCI 2000;92:328-32.
Ross et al, Results
Odds Ratio of Breast CA per 5 Years of Use
HRT Type
Odds Ratio
95% C.I.
No HRT
1.0
Referent
Any HRT
1.10
(1.02 – 1.18)
ERT
1.06
(0.97 – 1.15)
CHRT
1.24
(1.07 – 1.45)
SEPRT
1.38
(1.13 – 1.68)
CCRT
1.09
(0.88 – 1.35)
Thrombophilia
Relative Risk vs. Odds
Ratio
With
AV
fistula
W/O
AV
fistula
throm.
Yes
59
122
181
No
48
190
238
OR = (59/48)/(122/190)=1.91
RR = (59/181)/(48/238)=1.65
With
AV
fistula
W/O
AV
fistula
throm.
Yes
59
244
303
No
48
380
428
OR = (59/48)/(244/380)=1.91
RR = (59/303)/(48/428)=1.77
Tripepi G. Kidney International 2007
Number Needed to Treat (NNT)
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NNT is the number of patients needed to
treat to prevent one event or outcome
reciprocal of the absolute risk reduction
E.g. 0.30 – 0.05 = 0.25 = ARR
1/ARR = 1/0.25 = 4 = NNT
incorporates baseline risk w/o treatment
and risk reduction with treatment
clinically useful; tells how much effort
required to prevent one event
Number Needed to Treat
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Be cognizant of the “time” factor
The smaller the NNT, the more impressive the
result
Patients may have a different baseline risk than
the “average” study patient
Limitations
– Expressed as single number (point estimate)
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“True” NNT may be higher or lower
95% confidence intervals are useful
– NNT is 7 (95%CI 3 – 11)
– Need a binary outcome
Number Needed to Harm
(NNH) or (NNT:H)
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Number needed to treat to cause
harm to one more patient
1/absolute risk increase
Example
– Adverse event (>3X ULN AST or ALT)
Lipitor 10mg QD: 0.2%
 Lipitor 80mg QD: 1.2%
 1/0.01 = 100 NNH
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Number Needed to Treat
(NNT)
Disorder
Interven
tion
Events Being
Prevented
CER
EER
Follow
up time
NNT
DBP
115-129
BP
drugs
Death, stroke
or MI
13%
1.4%
1.5 yrs
8
DBP
90-129
BP
drugs
Death,
stroke, or MI
5.5%
4.7%
5.5 yrs
128
Sym
carotid
stenosis
CEA (vs.
medical
therapy)
Death or
major stroke
18%
8%
2 yrs
10
Mildmod Alz
Aricept
v. PBO
No functional
decline
44%
59%
1 yr
7
Renal
PO
Contrast
insuff/an mucomy
media
induced ↓ in
giogram
st v.
renal function
PBO
12%
4%
48 hrs
12
Putting it Together
McQuay, H. J. et. al. Ann Intern Med 1997;126:712-720
Don’t Forget…..
 Relative
risk reduction is
always larger, and “looks”
better than absolute risk
reduction
Confidence Intervals (CI)
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Provides a measure of precision (or
uncertainty) of an estimate (i.e.study
results) for making inferences about the
population of all such patients
95% CI
– 95% of such intervals will contain the true
population value
– Range of values within which we can be 95%
sure that the true value lies
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The smaller the study (i.e. less patients) the
wider the confidence intervals
Confidence Intervals
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CIs and significance tests are closely
related mathematically
A “significant” P value of <0.05 will
correspond to a 95% CI which
excludes the value indicating no
difference
– 0 for the difference between 2 means or
proportions
– 1 for a relative risk or odds ratio
Which of the following lipid parameters were significantly
changed in patients receiving the soy-containing diets?
Which quartile group is significantly different from the <30 group?
HRT and Breast Cancer
Nurses Health Study, 1978 to 1992
Hormone
Relative Risk
None
1.0
Conj. Estrogen
1.32
Other Estrogens
1.28
E+P
1.41
Progestins Alone
2.24
NEJM 1995;332:1589-93.
95% C.I.
reference
(1.14 - 1.54)
(0.97 - 1.71)
(1.15 - 1.74)
(1.26 - 3.98)
Hazard Ratio
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Compares the risk of event in two
populations
– A relative measure
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Ratio of risk in group 1 to risk in group
2
Assumption: “proportional hazards”
– “risk is constant over time”
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Used to analyze time-to-event curves
WHI Study Summaries
Hazard Ratio (95% CI)
Clinical Event
WHI (E+P)
WHI (E)
CHD events
1.29 (1.02-1.63) 0.91 (0.75-1.12)
Stroke
1.41 (1.07-1.85) 1.39 (1.10-1.77)
Pulmon. emb.
2.13 (1.39-3.25) 1.34 (0.87-2.06)
Breast CA
1.26 (1.00-1.59) 0.77 (0.59-1.01)
Colon CA
0.63 (0.43-0.92) 1.08 (0.75-1.55)
Hip fracture
0.66 (0.45-0.98) 0.61 (0.41-0.91)
Death
0.98 (0.82-1.18) 1.04 (0.88-1.22)
JAMA 2004;291:1769-71.
Intensive Lipid Lowering –
Acute Coronary Syndromes
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PROVE IT-TIMI 22 Study
Treatment: Pravachol 40mg QD (LDL goal
<100) vs. Lipitor 80mg QD (LDL goal~70)
– Statin naïve (75%): baseline TChol ≤240
– On statins (25%): baseline TChol ≤200
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N=4,162 with ACS in past 10 days
– Mean duration: 2 years
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Primary outcome: death (any cause), MI,
unstable angina, PTCI, or CABG
N Engl J Med 2004;350:1495-504.
PROVE IT - Results
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Mean LDL
– Pravachol 40mg: 106 (baseline)  95mg/dL
– Lipitor 80mg: 106 (baseline)  62mg/dL
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Primary outcome
– Pravachol 40mg: 26.3%
– Lipitor 80mg: 22.4%
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RRR 16%
ARR 3.9%
NNT 25.6
Baseline LDL ≥125mg/dL: 34% RRR
Baseline LDL <125m/dL: 7% RRR
P=0.02
Safety
– >3XULN ALT: Pravachol 40mg: 1.1%, Lipitor 80mg 3.3%
– DC med due to myalgias/CK: Pravachol 2.7%, Lipitor 3.3%
– DC rate: Pravachol (33%), Lipitor (30.4%)
N Engl J Med 2004;350:1495-504.
Intensive Lipid Lowering in Patients
with Stable Coronary Disease
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TNT Study
Treatment: Lipitor 10mg QD (LDL goal <100)
vs. Lipitor 80mg QD (LDL goal: 75 mg/dL)
– 8 week run-in of Lipitor 10mg QD
– Randomized if LDL <130
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N=10,001, median duration: 4.9 yrs
– History of MI, angina, and hx of revascularization
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Primary endpoint: CHD death, MI,
resuscitation after cardiac arrest, or stroke
N Engl J Med 2005;352:1425-35.
TNT Study - Results
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Mean LDL
– Lipitor 10mg: 98mg/dL (baseline) → 101mg/dL
– Lipitor 80mg: 97mg/dL (baseline) → 77mg/dL
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Primary outcome
– Lipitor 10mg: 10.9%
– Lipitor 80mg: 8.7%
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Mortality
RRR 22%
ARR 2.2%
NNT 45
– All-cause: HR 1.01 (0.85-1.19)
– Noncardiovascular:
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Lipitor 10mg (2.5%), Lipitor 80mg (3.2%) HR: 1.25 (0.99-1.57)
P=0.06
TNT – Cost Analysis
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Drug cost
– 10mg (1yr) $811; 10mg (4.9yrs) $3,974
– 80mg (1yr) $1,119; 80mg (4.9yrs) $5,484
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NNT = 45.4
– 45.4 X $5,484 = $248,980
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Incremental cost over 10mg QD
– $248,980 - $180,420 = $68,560
www.drugstore.com Aug 2005
Lipitor 80mg in PROVE-IT
and TNT
PROVE-IT
TNT
N=4162 N=10001
Yes
Yes
25.6
45.4
Yes
?
3.3%
1.2%
Significant increase in myalgias?
No
No
Increase in noncardiovascular
mortality?
No
Yes
Significant decrease in primary
outcome?
NNT (primary outcome)
Patients with highest LDL at baseline
observed greatest benefit?
>3XULN AST/ALT
CLASS Study
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Annualized incidence of upper GI ulcer
complications
– Celecoxib 0.76%
– NSAIDs 1.45%
– Relative risk 0.53 (0.26-1.11)
– Absolute risk reduction 0.69%
– NNT= 145
CLASS Study
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Annualized incidence of upper GI ulcer
complications plus symptomatic ulcers
– Celecoxib 2.08%
– NSAIDs 3.54%
– Relative risk 0.59 (0.38-0.94)
– Absolute risk reduction 1.46%
– NNT= 68.5
– Cost of preventing one event= $49,715
Vertebral Fractures
Absolute or Relative
Measure?
Absolute Risk
Absolute Risk Reduction
Relative Risk
Relative Risk Reduction
Odds ratio
Hazard ratio
Number need to treat or harm
Summary
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Distinguish between absolute and
relative (benefits or harms) drug
effects
– RRR looks “better” than ARR
– NNT is a useful measure
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Relative measures
– Odds ratio, relative risk, hazard ratio
<1: “protective” effect; lower risk
 1: no difference in risk
 >1: increased risk
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For the 3 abstracts
determine…..
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ARR
NNT
RR
RRR
NNT 5.0 (4.1-6.9)
NNT 3.1 (2.6-3.8)
Pain 1997;70:193-201
A
B
C
D
Clinically
significant??
Study B (Hypertension)
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Fatal or nonfatal stroke
– Placebo (CER): 17.7%
– Indapamide (EER) 12.4%
– ARR: 17.7 – 12.4 = 5.3%
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NNT = 1/0.053 = 18.9 or 19 (over 18 mon.)
– Relative risk: .124/.177 = 0.7
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Reported HR: 0.7 (0.49 – 1.01)
– RRR: 1 – 0.7 = 0.3 or 30%
Study C (diabetes)
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Nonfatal MI, nonfatal stroke, or CV death
– Standard tx (CER): 7.2%
– Intensive tx (EER): 6.9%
– ARR: 7.2 – 6.9 = 0.3%
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NNT: 1/0.003 = 333
– Relative risk: 0.069/0.072 = 0.96
– RRR: 1 – 0.96 = .04 or 4%
– Statistically nonsignificant result
Study D (DVT prophylaxis)
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Any DVT, nonfatal PE, or death
– Enoxaparin (CER): 18.9%
– Rivaroxaban (EER): 9.6%
– ARR: 18.9 – 9.6 = 9.3%
– NNT = 1/0.093 = 10.8 or 11 (over 17 days)
– Relative risk: 0.096/0.189 = 0.51 or 51%
– RRR: 1 – 0.51 = 0.49