Transcript 1.2

It is 1950. Dr. L. Craven specializes in treatment of
arthritis. Many of his patients receive aspirin and he
notes that the incidence of myocardial infarction (heart
attack) is lower than expected in these patients.
Craven LL: Acetylsalicylic acid, possible preventive coronary
thrombosis. Ann. West. Med. Surg. 4:95-99, 1950.
Craven LL: Experiences with aspirin (acetylsalicylic acid) in
the nonspecific prophylaxis of coronary thrombosis. Miss.
Valley Med. J. 75:38-44, 1953.
What type of study?
1.
2.
3.
4.
5.
Case series
Case-control
Retrospective cohort
Prospective cohort
Clinical trial
20%
20%
20%
20%
20%
Coronary Drug Project, 1976
• 1529 patients with a history of myocardial infarction,
most of them several years earlier.
• Randomly assigned (double-blind) to aspirin therapy 324-mg tablet three times daily or placebo treatment.
• Length of follow-up ranged from 10-28 months (average
22 months).
Coronary Drug Project, 1976
CHD Mortality
Yes
No
Aspirin
35
723
758
Placebo
49
722
771
How would you analyze these data?
RR = 35/758 = 0.73 (0.48-1.11)
49/771
p=0.14
Interpretation? Conclusions?
4.6%
6.4%
Coronary Drug Project, 1976
Definite Non-fatal MI
Yes
No
Aspirin
28
730
758
Placebo
32
739
771
RR = 28/758 = 0.89 (0.54-1.45)
32/771
p=0.65
Interpretation? Conclusions?
Coronary Drug Project, 1976
“This difference is suggestive of a beneficial
effect for aspirin in the treatment of post-MI
men, but not large enough to be conclusive.”
Mayo Clinic Proceedings, 1978
Primary prevention in 473 patients with arthritis?
 Followed arthritis patients on aspirin
and determined MI, angina, stroke rates.
 Compared to overall rates “in the
community” (unpublished data).
Overall, no difference in observed and expected rates of any outcome.
However, in men there were 30-50% reductions (but NSD).
MI in men: Expected 7.2; observed 5
(30% reduction)
A variety of case-control and cohort type studies with
relatively small numbers of subjects suggested that aspirin
might reduce coronary “events” by perhaps 20-30%, and it
might be beneficial in primary prevention, but none of the
observational studies had been conclusive.
What were the major limitations of
all of these observational studies?
1. Small sample size; limited power to detect a
modest difference
2. Potential biases: misclassification, selection
bias, recall bias
3. Uncontrolled confounding: many other factors
influence risk of heart disease
What should be done to determine
whether aspirin is effective in primary
prevention of cardiovascular disease?
How would you do it?
Preventive RCTs
Keep healthy people well
Does tamoxifen lower the incidence of
breast cancer in women with high
risk profile compared to high risk
women not given tamoxifen?
Therapeutic RCTs
Treat (or cure) disease
Do combinations of 2 or 3 antiretroviral
drugs prolong survival of AIDS
patients better than single drugs?
New Drug Trials
Phase I
 Preliminary information on safety
Phase II
 Efficacy; dosage
 Additional data on safety & side-effects
Phase III
 Advantage over existing treatments
Phase IV
 Post-marketing surveillance
Back to Aspirin –
Is it ethical to do this?
Equipoise: Will the new treatment be better?
Maybe; Maybe not.
Sufficient belief to justify
exposing some subjects
to new treatment.
Sufficient doubt to
justify withholding new
treatment from some
subjects.
Institutional Review Board Approval
Required for all research involving human
subjects (not just clinical trials).
“Human Research” means a systematic investigation
involving living humans (including research development,
testing and evaluation), designed to develop or contribute
to generalizable knowledge.
Benefits
Risks
Who should we invite to participate?
(age, gender, occupation?)
Inclusion/exclusion criteria?
Selection of Study Population
Reference population –
The general group to whom results should be
applicable.
• All humans
• Women with breast cancer
• Men at risk for MI
Study or experimental population –
Potential participants (people considered for
enrollment).
• Breast Cancer patients at BUMC
• U.S. Physicians
• U.S. Health Professionals
What groups will be compared?
Are you going to use a placebo?
Why or why not?
Is it ethical to use a placebo?
Why Use A Placebo?
• Minimize bias in assessing outcomes
• Makes groups as comparable regarding
the perception of treatment.
• Allows “blinding” (not always possible).
Blinding (or Masking)
Exposure status is unknown.
Minimizes bias in assessing outcomes
 Single-blind: subjects unaware of treatment group
 Double-blind: subjects and investigators unaware
Pain relief
>20%
Glucosamine +
Chondroitin
211
Minimal
Effect
106
Total #
Subjects
317
211/317 = .666 = 67/100
From Clegg DO, et al.:Glucosamine, chondroitin sulfate, and the two in
combination for painful knee osteoarthritis. N Engl J Med 354:795, 2006.
Placebo
Anti-inflam. drug
Glucosamine
Chondroitin
Glucosamine +
Chondroitin
Pain relief
Minimal
>20%
Effect
188
125
223
95
203
114
208
110
211
106
Total #
Subjects
313
318
317
318
317
Glucosamine + Chondroitin: 211/317 = 67%
Placebo: 188/313 = 60%
The “placebo
effect”
What can you conclude?
How would you go about making a formal comparison?
From Clegg DO, et al.:Glucosamine, chondroitin sulfate, and the two in
combination for painful knee osteoarthritis. N Engl J Med 354:795, 2006.
How many should we invite?
Statistical power: the ability of a study to demonstrate
a statistically significant association, if one exists.
• How many will have expected end points?
Restrict study to persons at higher risk?
• Duration of Follow-up: Is there sufficient time
to accumulate end points?
• Acute vs. long-term effects of treatment.
• Do you need multiple study sites?
Sample Size Estimates
What do we do after we have a
group of willing subjects?
Informed consent?
(What is informed consent)?
Informed Consent
Informed about:
 Treatments
 Potential outcomes; risks/benefits
 Randomization (i.e., treatment is
not their choice)
 What is required of them
Obtain informed consent prior to randomization.
How should subjects be assigned
to the comparison groups?
Randomization
Method of assignment such that each individual has an
equal chance of receiving each possible treatment.
Equal chance:
 Coin toss
 Random numbers (table or computer)
Other methods have potential problems
 Subject self-selects
 Day of week, order of visit, etc.
Benefits/Strengths:
• Unpredictability
• Leads to comparability
 Balance of known & unknown confounders
 Minimizes selection bias
Large, carefully done randomized clinical trials
are particularly useful for assessing moderate or
small effects which may be clinically important.
1. Random assignment of a sufficiently large
number of subjects provides exquisite
control over both known and unsuspected
confounding factors.
2. A large sample size increases the ability to
identify modest, but significant differences.
Population
Hierarchy
Reference
Population
Experimental Population
(potential participants)
Participants
Non-participants
(willing and eligible)
Allocation
Active Intervention Group
 Compliers
 Non-compliers
Comparison Group
 Compliers
 Non-compliers
Ok, so now the trial is under way and
they plan to follow subjects for 8 years.
Anything else we should do while we are
waiting for the results?
What about maintaining compliance
(adherence to the protocol) and follow up?
Does compliance matter?
What steps can you take to
maintain compliance and follow up?
How do you know if they have complied?
Maintaining Compliance & Follow-up
• Following assigned protocol for the duration of the study
is crucial to ability to demonstrate a true effect.
• Noncompliance makes the groups more alike & reduces
the ability to detect a difference (bias towards null).
 Begin with a motivated, knowledgeable group.
 Identify subjects who are unlikely / unable to comply.
 Make the protocol as simple as possible.
 Be clear about what is involved.
 If possible, mask the treatment so all groups comply.
 Maintain frequent contact with subjects without
interfering with treatment.
 Provide incentives (free check-ups, transportation, etc.)
 Conduct a “run-in” or “lead-in” period before the real trial.
Assessing Compliance
Assess compliance, if possible.
 Self-report
 Pill counts
 Biological measures (blood, urine)
Non-compliance Tends to Bias
Toward the “Null”
“Null” means
no difference
0.3 0.5
1.0
Relative Risk
2
3
What about monitoring for safety?
Data and Safety
Monitoring Board
A scientifically & financially independent
group with expertise in various disciplines
charged with safeguarding participants.
Reviews progress of trial & data on outcome
 Interim results
 Adverse events
Can recommend modification or termination of all/part of trial.
 Treatment results so good cannot withhold from others.
 Treatment side effects/outcome so bad cannot continue.
Physicians' Health Study
•
Randomized, double-blind, placebo controlled trial.
•
Primary prevention of CVD & cancer in 22,071
U.S. male physicians, aged 40-84 at baseline.
•
A 2x2 factorial design to test:
• 325 mg aspirin on alternate days
• 50 mg beta carotene on alternate days
Physicians' Health Study
Exclusion Criteria




History of:
• Heart attack
• Stroke
• Cancer
• Current liver or kidney disease
• Peptic ulcer or gout
Contraindication to aspirin
Current use of aspirin or other drugs
affecting platelet function
Current use of a vitamin A or b carotene
Physicians' Health Study
261,248 invitation letters sent with questionnaire
112,528 questionnaires returned
59,285 willing to participate
33,223 eligible and enrolled in 18-week run-in
phase on active ASA & b-carotene placebo.
22,071 randomized
Randomization Scheme
2x2 factorial design
22,071 U.S.
Male Physicians
aged 40-84
Aspirin
11,037
b-carotene
5,517
Both
Aspirin Placebo
11,034
b-carotene
placebo
5,520
b-carotene
5,519
b-carotene
placebo
5,515
Aspirin
b-carotene
Neither
How can we tell if randomization was successful?
What are some known risk factors for heart disease?
Were these confounding factors distributed equally?
Baseline Characteristics
Age (yrs)
Systolic BP (mmHg)
Diastolic BP (mmHg)
History of hypertension (%)
History of high cholesterol (%)
Cholesterol level (mg)
History of diabetes (%)
History of angina (%)
Parental MI (%)
Aspirin
(n=11,037)
Placebo
(n=11,034)
53.2  9.5
126.1  11.3
78.8  7.4
13.5
17.5
212.1  44.2
2.3
1.3
13.0
53.2  9.5
126.1  11.1
78.8  7.4
13.6
17.3
212.0  45.1
2.2
1.2
13.1
Baseline Characteristics
Current smoking (%)
Past smoking (%)
Daily alcohol (%)
Exercise >1/week (%)
Body mass index (kg/m2)
Multivitamin
Aspirin
(n=11,037)
Placebo
(n=11,034)
11.0
39.4
24.9
71.7
24.9  3.1
19.9
11.1
39.1
25.0
71.2
24.9  3.0
19.9
How will we analyze the data?
Basic analysis is that of a cohort study
(i.e. – compare incidence….)
Should we include all subjects in the analysis?
Compliance
After 60.2 months
Aspirin group
85.71% took treatment
as intended
Placebo Group
14.23% took aspirin or other
platelet-active drugs
Who should we include in our analysis?
Intention to Treat Analysis
Primary analysis: “Intention to treat”
 For the primary analysis all subjects should be
included in the groups to which they were
randomly assigned, even if they did not complete
or even receive the appropriate treatment.
•
•
•
Preserves baseline comparability & control of
confounding
Since compliers and non-compliers may be
systematically different it prevents bias.
It reflects efficacy in everyday practice.
Secondary analysis: Compliers only.
 Not a randomized comparison.
Fatal Myocardial Infarction
Yes
No
Aspirin
10
11,027
11,037
Placebo
26
11,008
11,034
Use “Epi_Tools.xls” to calculate the risk
ratio, the p-value, & 95% CI.
Interpret your findings in words.
Non-fatal Myocardial Infarction
Yes
No
Aspirin
126
10,911
11,037
Placebo
213
10,821
11,034
Use “Epi_Tools.xls” to calculate the risk
ratio, the p-value, & 95% CI.
Interpret your findings in words.
Follow-up After 60.2 Months
aspirin
placebo
Morbidity follow-up
Vital status only
Mortality follow-up
Compare
Incidence
of disease
99.7%
0.3%
100.0%
Stroke & Total CV Deaths
Aspirin
Group
Placebo
Group
RR
95% CI
Total Stroke
119
98
1.22
(0.93-1.60)
Total CV Deaths
81
83
0.96
(0.60-1.54)
More follow-up needed, but . . .
Data & Safety Monitoring Board
On December 18, 1987, the Data &
Safety Monitoring Board
recommended early termination of
the aspirin component of the trial.
Aspirin Placebo
(/10,000)
Myocardial Infarction
125.9
RR
(/10,000)
216.6
0.58
What should we recommend?
Benefit vs. Risks
Aspirin Placebo
(/10,000)
RR
(/10,000)
Myocardial Infarction
125.9
216.6
0.58
Stroke
107.8
88.8
1.2
Ischemic
82.4
74.3
1.1
Hemorrhagic
20.8
10.9
1.9
153.1
125.1
1.2
34.4
19.9
1.7
2699.1 2037.3
1.3
Upper GI ulcer
with hemorrhage
Bleeding
Transfusion need
43.5
25.4
What should we recommend?
1.7
Benefit vs. Risks
Aspirin Placebo
(/10,000)
RR
(/10,000)
RD
(/10,000)
Myocardial Infarction
125.9
216.6
0.58
-91
Stroke
107.8
88.8
1.2
19
Ischemic
82.4
74.3
1.1
8
Hemorrhagic
20.8
10.9
1.9
10
153.1
125.1
1.2
28
34.4
19.9
1.7
15
2699.1 2037.3
1.3
690
1.7
18
Upper GI ulcer
with hemorrhage
Bleeding
Transfusion need
43.5
25.4
Benefit vs. Risks
Aspirin Placebo
(/10,000)
RR
(/10,000)
RD
(/10,000)
Myocardial Infarction
125.9
216.6
0.58
-91
Stroke
107.8
88.8
1.2
19
Ischemic
82.4
74.3
1.1
8
Hemorrhagic
20.8
10.9
1.9
10
153.1
125.1
1.2
28
34.4
19.9
1.7
15
2699.1 2037.3
1.3
690
1.7
18
Upper GI ulcer
with hemorrhage
Bleeding
Transfusion need
43.5
25.4
Results Of The Physicians' Health Study
 Clear benefit of aspirin on risk of myocardial
infarction in male physicians.
 Unable to evaluate aspirin's effect on stroke or
total cardiovascular mortality, due to early
termination of the trial.
 In primary prevention, aspirin should be
prescribed on an individual basis by the health
care provider as an adjunct to, not an alternative
to, the management of other risk factors.
Why Were Women Physicians Not
Included in the Physicians' Health Study?
Sample size:
 Only 1 out of 10 physicians over 40
years were women in 1982.
 By age 60 women have only 1/3 the
# of cardiovascular events as men.
External Validity
(Generalizability)
Unable to say whether aspirin is effective in
women or if the effect is different in women.
And…
The effect of aspirin did turn out to be different in men &
women.
Low-dose aspirin reduced strokes in healthy women,
but had no effect on heart attacks unless the women
were >65 years old.
Double cheeseburger,
large fries, jumbo
coffee… oh, and an
aspirin – gotta take
care of the old ticker,
ya know.
“Take an aspirin every day, but before you
swallow it, take it for a five-mile walk.”
Community Trials
Entire communities can be assigned
to a treatment or intervention.
Does fluoridation of water prevent
dental caries? (1944 - The
Newburgh-Kingston Caries Trial)
35 miles
Herd immunity in adults against influenza-related illnesses with use
of the trivalent-live attenuated influenza vaccine (CAIV-T) in children.
Pedro A. Piedra et al.: Vaccine 2005;23:1540–1548.
School children have the highest attack rates for influenza, and many
observers believe that student proximity in classrooms promotes the
spread of the influenza virus. Infected children then infect family
members. Studies in Michigan and Japan suggested that influenza
immunization programs in children reduced mortality and morbidity in
adults, because school-to-home transmission was reduced. The
study cited above tested this by conducting a childhood immunization
program in two communities (Temple and Belton) and measuring
subsequent rates of influenza in adults. About 20-25% of eligible
children were vaccinated. The adult rates of influenza in the test
communities were compared to adult rates of influenza in three
communities that did not have childhood immunization programs
(Waco, Bryan, and College Station).
Handwashing
“Every year, more than 3.5 million children aged less than 5 years
die from diarrhea and acute lower respiratory-tract infection. These
deaths are concentrated in low-income communities in developing
countries. Several studies have shown that regular hand washing
with soap reduces the incidence of diarrhea in children younger than
5 years in communities with a high incidence of diarrhea, although
we are unaware of any reports of the effect of hand washing on
acute respiratory-tract infections in settings where pneumonia is a
leading cause of death.
In developed countries, the promotion of hand washing has
reduced respiratory-tract infections in several settings....”
 What gap in the existing knowledge base on the control of
serious infections of childhood is this excerpt describing?
 What hypothesis needs to be tested?
“We undertook the Karachi Soap Health Study… to measure
the broad health benefits brought about by improvement of
handwashing and bathing with soap in settings where
communicable diseases are leading causes of childhood
morbidity and mortality.”
 How would you design a study to accomplish this goal, specifically
focusing on pneumonia?
– What epidemiologic study design would you use.
– What would be the main exposure variable, and
what would be the main outcome variable?
 This study will be set in Karachi, the largest city in Pakistan. Briefly
describe the study population you would use for your study.
“Fieldworkers identified 42 candidate neighbourhoods separated by
a street or market area. Eligible households were located in a
candidate neighbourhood, had at least two children younger than
15 years (at least one of whom was less than 5 years old), and
were planning to continue to reside in the same home for the
duration of the study….”
“Overall, 25 neighborhoods were assigned to hand washing
promotion and 11 to control.”
Within neighborhoods candidate households continued to be enrolled
by random selection until there were 600 hand washing households
(300 regular soap; 300 antibacterial soap) and 300 control
households.
“Hand washing promotion was assigned at the neighbourhood level,
because several activities promoting hand washing were
undertaken at this level.”
 It is notoriously difficult to get people to wash their hands
thoroughly and consistently. (Disturbingly enough, physicians
are among the worst offenders.) How would you consider
promoting hand washing for this study?
“During the week before soap was distributed and disease
surveillance was begun, fieldworkers gathered participants [in
groups of 10-15 households] … for neighborhood meetings that
lasted 30-45 minutes.”
They provided slide shows, showed videotapes and distributed
pamphlets to illustrate health problems resulting from not washing
and to provide specific hand washing instructions
For the first 2 months they held neighborhood meetings 2-3 times per
week. In months 3-9 the meetings occurred weekly. Field workers
also visited intervention households weekly to observe/correct hand
washing procedures and to encourage adherence. Field workers
encouraged all family members to wash after defecation, after
cleaning an infant, before preparing food, before eating, and before
feeding an infant. They also encouraged subjects to bathe once a
day with soap and water.
“Field workers provided control families with a regular supply of
books, notebooks, pens, and pencils to help their children’s
education, but they gave no products that would be expected to
affect rates of respiratory illness, diarrhea, or impetigo. Field
workers neither encouraged nor discouraged hand washing in
control households, and visited both control and intervention
households with equal frequency.”




What data will you collect?
What are the key comparisons you would make?
What calculations will you do?
How will you measure “association”?
Table to report pneumonia results for Karachi Soap Health Study
New cases of pneumonia Person time at risk
Plain soap
# cases
20,009
Antibacterial soap
# cases
20,191
No intervention (control)
# cases
18,392
Incidence rates of pneumonia in children younger than 5 years
Antibacterial soap
Plain soap
Control
4.21 per 100 person-weeks
4.16
“
8.50
“
What do you conclude about the efficacy of hand
washing in preventing pneumonia in young children?
Luby SP, Agboatwalla M, Feikin DR, Painter K, Billhimer W, Altaf
A, Hoekstra RM. Effect of handwashing on child health: a
randomized controlled trial. Lancet 2005;366:225-33.
 Do these findings have any relevance for measures to deal with
the threat of a flu pandemic?
 What implications do these findings have for disease control in
the US?
Hand washing is a simple, highly effective
way to prevent common gastrointestinal
and respiratory diseases!
Pneumonia Results for Karachi Soap Health Study
Comparison
Data
IRR
Antibacterial soap vs control
2.42/4.40
0.55
Plain soap vs control
2.20/4.40
0.50
Plain soap vs antibacterial soap
2.42/2.20
1.1
 Compare the efficacy of handwashing in preventing pneumonia
in infants under 1 year old, children 1-2 years old, and children
2-5 years old? What do you think might explain the differences
between age groups?
“Provision of free soap, frequent community meetings, and weekly
household handwashing promotion visits to all impoverished
households worldwide is prohibitively expensive.
 As public health professionals, how can we find cost-effective
techniques for handwashing promotion?
Luby SP, Agboatwalla M, Feikin DR, Painter K, Billhimer W,
Altaf A, Hoekstra RM. Effect of handwashing on child health: a
randomized controlled trial. Lancet 2005;366:225-33.
 Compare the effectiveness of handwashing in preventing pneumonia
in infants under 1 year old, children 1-2 years old, and children 2-5
years old? What do you think might explain the differences between
age groups?
 Summarize the data in this graph. What do you think explains
what you see here?