applied interpretation of clinical studies jim hoehns, pharm.d., bcps, fccp
TRANSCRIPT
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 Fatality risk per 100,000 person-
yearsAspirin prophylaxis in 50 y.o. men
10.4
Clozapine for schizophrenia 35Rofecoxib (Vioxx) for arthritis pain
76
Passenger in car 11Driving motorcycle 450Firefighter 10.6Semi-truck driver 44.8Rock climbing 36
Cohen JT. Health Aff 2007;25:636-46.
Outline
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 = SafetyT = Tolerability
“Pooled drop-out rates” E = Effectiveness -- Studies
showing that the new drug is better than your current choice
P = PriceS = 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…
Examples:– Safety and efficacy trials: response
rate, median survivals– Comparative trials: odds ratio,
hazard ratio
Elizabeth S. Garrett, Ph.D.
Which Looks Better?
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 Risk is the probability or frequency of
an outcome Migraine medication (6 mon.)
– Placebo: 30% recurrence Control event rate (CER)
– Drug M: 5% recurrence Experimental event rate (EER)
Absolute risk reduction (ARR)– CER – EER = ARR– 30% - 5% = 25%
Absolute Risk Reduction Helps discriminate huge
treatment effects from small ones– Preserves information on the
baseline risk– Clinically meaningful information
Relative Risk and Relative Risk Reduction
Relative Risk - risk in treatment group relative to that in control group– 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
Measures risk of developing condition over a specified time
Relative Risk
Relative Risk = Risk of the outcome if the risk factor is present
Risk of the outcome if the risk factor is absent
Example:Breast CA No Breast CA
Estrogen Tx:
No Estrogen Tx:
a = 80 b = 920
c = 10 d = 990
Relative Risk =
aa + b
cc + d
= 8
Odds Ratio
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 Ratio = Odds of being on HRT if Breast CA present
Odds of being on HRT if Breast CA not present
Example:Breast CA No Breast CA
Estrogen Tx:
No Estrogen Tx:
a = 80 b = 920
c = 10 d = 990
OR = a / cb / d
= 8.6
Ross et al.
Case-control study in Los Angeles– 1897 cases with incident breast CA
1637 controls– matched on age, race-ethnicity,
neighborhood 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
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)
Odds Ratio of Breast CA per 5 Years of Use
Relative Risk vs. Odds Ratio
With AV
fistula
W/O AV
fistula
throm.
With AV
fistula
W/O AV
fistula
throm.
Yes 59 122 181 Yes 59 244 303
No 48 190 238 No 48 380 428
OR = (59/48)/(122/190)=1.91RR = (59/181)/(48/238)=1.65
OR = (59/48)/(244/380)=1.91RR = (59/303)/(48/428)=1.77
Th
rom
bop
hili
a
Tripepi G. Kidney International 2007
Number Needed to Treat (NNT)
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 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) “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) 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
Number Needed to Treat (NNT)Disorde
rIntervention
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 stenosi
s
CEA (vs.
medical
therapy)
Death or major stroke
18% 8% 2 yrs 10
Mild-mod Alz
Aricept v. PBO
No functional
decline
44% 59% 1 yr 7
Renal insuff/angiogra
m
PO mucomyst v. PBO
Contrast media
induced ↓ in renal function
12% 4% 48 hrs 12
McQuay, H. J. et. al. Ann Intern Med 1997;126:712-720
Putting it Together
Don’t Forget…..
Relative risk reduction is always larger, and “looks” better than absolute risk reduction
Confidence Intervals (CI) 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 The smaller the study (i.e. less
patients) the wider the confidence intervals
Confidence Intervals
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
Hormone Relative Risk 95% C.I.
None 1.0 reference Conj. Estrogen 1.32 (1.14 - 1.54)
Other Estrogens 1.28 (0.97 - 1.71) E + P 1.41 (1.15 - 1.74)
Progestins Alone 2.24 (1.26 - 3.98)
Nurses Health Study, 1978 to 1992
NEJM 1995;332:1589-93.
Hazard Ratio
Compares the risk of event in two populations– A relative measure
Ratio of risk in group 1 to risk in group 2
Assumption: “proportional hazards”– “risk is constant over time”
Used to analyze time-to-event curves
WHI Study Summaries
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.
Hazard Ratio (95% CI)
Intensive Lipid Lowering – Acute Coronary Syndromes
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
N=4,162 with ACS in past 10 days– Mean duration: 2 years
Primary outcome: death (any cause), MI, unstable angina, PTCI, or CABG
N Engl J Med 2004;350:1495-504.
PROVE IT - Results Mean LDL
– Pravachol 40mg: 106 (baseline) 95mg/dL– Lipitor 80mg: 106 (baseline) 62mg/dL
Primary outcome– Pravachol 40mg: 26.3%– Lipitor 80mg: 22.4%
Baseline LDL ≥125mg/dL: 34% RRR Baseline LDL <125m/dL: 7% RRR
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%)
RRR 16%ARR 3.9%NNT 25.6
P=0.02
N Engl J Med 2004;350:1495-504.
Intensive Lipid Lowering in Patients with Stable Coronary Disease
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
N=10,001, median duration: 4.9 yrs– History of MI, angina, and hx of
revascularization Primary endpoint: CHD death, MI,
resuscitation after cardiac arrest, or stroke
N Engl J Med 2005;352:1425-35.
TNT Study - Results Mean LDL
– Lipitor 10mg: 98mg/dL (baseline) → 101mg/dL– Lipitor 80mg: 97mg/dL (baseline) → 77mg/dL
Primary outcome– Lipitor 10mg: 10.9%– Lipitor 80mg: 8.7%
Mortality– All-cause: HR 1.01 (0.85-1.19)– Noncardiovascular:
Lipitor 10mg (2.5%), Lipitor 80mg (3.2%) HR: 1.25 (0.99-1.57) P=0.06
RRR 22%ARR 2.2%NNT 45
TNT – Cost Analysis
Drug cost– 10mg (1yr) $811; 10mg (4.9yrs)
$3,974– 80mg (1yr) $1,119; 80mg (4.9yrs)
$5,484 NNT = 45.4
– 45.4 X $5,484 = $248,980 Incremental cost over 10mg QD
– $248,980 - $180,420 = $68,560www.drugstore.com Aug 2005
Lipitor 80mg in PROVE-IT and TNT
PROVE-ITN=4162
TNTN=1000
1Significant decrease in primary outcome?
Yes Yes
NNT (primary outcome) 25.6 45.4
Patients with highest LDL at baseline observed greatest benefit?
Yes ?
>3XULN AST/ALT 3.3% 1.2%
Significant increase in myalgias? No No
Increase in noncardiovascular mortality?
No Yes
CLASS Study
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
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 RiskAbsolute Risk ReductionRelative RiskRelative Risk ReductionOdds ratioHazard ratioNumber need to treat or harm
Summary
Distinguish between absolute and relative (benefits or harms) drug effects– RRR looks “better” than ARR– NNT is a useful measure
Relative measures– Odds ratio, relative risk, hazard ratio
<1: “protective” effect; lower risk 1: no difference in risk >1: increased risk
For the 3 abstracts determine….. ARR NNT RR RRR
Pain 1997;70:193-201
NNT 5.0 (4.1-6.9)
NNT 3.1 (2.6-3.8)
AB
CD
Clinicallysignificant??
Study B (Hypertension) Fatal or nonfatal stroke
– Placebo (CER): 17.7%– Indapamide (EER) 12.4%– ARR: 17.7 – 12.4 = 5.3%
NNT = 1/0.053 = 18.9 or 19 (over 18 mon.)
– Relative risk: .124/.177 = 0.7 Reported HR: 0.7 (0.49 – 1.01)
– RRR: 1 – 0.7 = 0.3 or 30%
Study C (diabetes)
Nonfatal MI, nonfatal stroke, or CV death– Standard tx (CER): 7.2%– Intensive tx (EER): 6.9%– ARR: 7.2 – 6.9 = 0.3%
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) 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