Pharmacoepidemiology Part 1

General Study Design Considerations y g

Yu-Xiao Yang, MD, MSCE, FACP g, , ,
Center for Clinical Epidemiology and Biostatistics University of Pennsylvania School of Medicine

CCEB

Outline
Background and Definitions g Study Designs in Pharmacoepidemiology
Randomized controlled trials Observational studies

CCEB

 A desire to take medications is, perhaps, the greatest feature which distinguishes man from di ti i h f other animals. animals.
Sir William Osler 1891 Osler,

CCEB

Pharmacoepidemiology
Pharmacologystudy of the effects of drugs g Clinical Pharmacologystudy of the effects of drugs in humans g
Pharmacokineticsbody effect on the drug Pharmacodynamicsdrug effect on the body

Epidemiologystudy of the distribution and determinants of diseases in populations

CCEB

Pharmacoepidemiology
Focus of inquiry is clinical pharmacology using the methods of epidemiology
Epidemiology Population:
Taco eaters

Pharmacoepidemiology Population:
HTN patients

Exposure:
Green peppers

Exposure:
ACE inhibitors

Outcome:
Infection

Outcome:
Cough

CCEB

Pharmacoepidemiology
the study of the use and effects of medications in populations pp the application of the methods of clinical epidemiology to address the subject matter of clinical pharmacology h l the science underlying the public health practice of drug safety surveillance
CCEB

Options in Research Design

Analytic Studies Experimental Study Prospective Cohort Study Retrospective Cohort Study

Case-Control Study Descriptive Studies p Analyses of Secular Trends Case Series Case Reports
CCEB

Options in Research Design

Analytic Studies Experimental Study Prospective Cohort Study Retrospective Cohort Study

Case-Control Study Descriptive Studies p Analyses of Secular Trends Case Series Case Reports
CCEB

Study Design in Pharmacoepidemiology

Formal studies
RCTs rare RCTs
Ethical concerns Time and funding constraints

Metaanalysis of RCTs M t l i f RCT Observational studies most common

CCEB

CCEB

RCT s RCTs in Pharmacoepidemiology

Background: Uncertain risk/benefit of HRT in women despite observational data This trial found that, compared with placebo, women receiving estrogen plus progestin experienced i i t l ti i d
increased risk of myocardial infarction increased risk of stroke increased risk of blood clots, including DVT and PE clots increased risk of breast cancer decreased risk of colorectal cancer fewer fractures

CCEB

RCT s RCTs in Pharmacoepidemiology

Background: Experimental and observational data suggest PPI therapy may reduce the protective effect of clopidogrel against coronary artery disease

The Cogent Trial g

CCEB
N Engl J Med 2010;363:1909-17

RCT s RCTs in Pharmacoepidemiology

CCEB

The Cogent Trial

Say what?

CCEB

Metaanalysis of RCTs

Metaanalysis of 42 trials In the rosiglitazone group, as compared with the control group, t l OR for myocardial infarction 1.43 (95% CI 1.03 to 1.98) OR for CV death 1.64 (95% CI, 0.98 to 2.74)

CCEB

Pharmacoepidemiology Observational Studies

Large number of diverse real-life users can be studied Made possible by electronic databases I Inexpensive i Useful for hypothesis-generation, strengthening or testing testing Generation of preliminary data M b the only feasible design in May be th l f ibl d i i some instances
CCEB

Pharmacoepidemiology Observational Studies

Key steps
Good study question Forming a research team Choice of data source Defining study cohort D fi i t d h t Choice of study design Defining exposure Defining outcomes Obtain funding (optional) Data collection Data analysis Publication P bli ti

CCEB

Typical Research Team

Principal Investigator
U Usually a clinical pharmacist or physician ll li i l h i t h i i

A Ph.D. level biostatistician

May or may not require funding

A programmer familiar with database management

Generally requires funding

Trainees in medicine, pharmacology, or ,p gy, epidemiology

Free!

CCEB

Defining Source Cohort

Often dictated by the data source Should be relevant for the study question
Exposure Outcome

CCEB

Choice of Study Design

Case-control vs. cohort study
CaseCase-Control Study Disease Present Co ohort Stu udy Present Absent

Exposur re

A C

B D

Absent Ab

CCEB

Cohort Study
persontime
26 14 17 26
NonNon random process

Exposed Unexpose d

26 22 24 20 26 26

CCEB

Study y population

Observation Period = Study outcome

Advantages of Cohort Study

More intuitive design the case-control Analogous to RCT Ca cu at o of c de ce possible Calculation o incidence poss b e Simultaneous assessment of multiple outcomes Viewed more favorably by some reviews and editors

CCEB

Choice of Study Design

Is cohort study always better than CC study?

CCEB

Choice of Study Design

Relevant questions
Incidence data desired? Multiple exposures or levels of exposure of interest? i t t? Multiple outcomes of interest? N Narrower confidence interval desired? fid i l d i d?

CCEB

Choice of Study Design

CC design is a more commonly used study design pharmacoepidemiology t d d i h id i l studies why?
Effi i Efficiency, efficiency and efficiency ffi i d ffi i Dose D Duration i Recency (e.g., current vs. past use) Different formulations

CCEB

The sophisticated use and understanding of f case-control case control studies is the most outstanding
methodologic

development of modern epidemiology. id i l Kenneth J. Rothman

CCEB

because it need not be extremely expensive nor timeconsuming to conduct a casecontrol study, many studies have study been conducted by would-be would be investigators who lack even a g rudimentary appreciation for epidemiologic principles. id i l i i i l Kenneth J Rothman J.
CCEB

Case-control study: The observational y epidemiologic study of persons with the disease of interest and a suitable control group of persons without the disease. The relationship of an attribute [risk factor] to the disease is examined by comparing the diseased and nondiseased with regard to how frequently the attribute [risk factor] is present.
John M. Last, Dictionary of Epidemiology CCEB

Why Conduct Case CaseControl Studies

Efficient to study multiple exposures for f a single outcome i l t Often less expensive than cohort study
Disease is rare Exposure data are expensive to collect There is a long latency or induction period

CCEB

Case-control Study C t l St d
Source Population Outcome A Study sample
Observed outcome

Exposure p with A Analysis of exposure with and without A Exposure p without A

Without t out Outcome A

Interpret Risk Odds Ratio O

CCEB

If a case-control study is conducted within an enumerated d t d ithi t d source population (which minimizes the possibility of selection bias), it can be thought of as a nested case-control study.
CCEB

Source Cohort
The "source cohort" behind a case-control study is casethe population (cohort) that gave rise to the cases included in the study. study Example: E l Cases: Cases: lung cancer cases listed in the cancer registry g g y of the State of Pennsylvania Source cohort: ? cohort:

CCEB

Selection of Cases
Ideally include all the cases in the defined population however in practice rarely done (and not necessary to draw valid conclusion). Most studies use sample of patients selected from some convenient source: often from persons seeking medical care for the disease disease. Better to use incident rather than prevalent cases.

CCEB

Selection of Controls
Controls are people who do not have the disease but are otherwise comparable to the cases. p Need to pick subjects who would have become cases in the study had they developed the disease: i.e. they are representative of the underlying p p population. Must be selected independent of exposure status.

CCEB

Odds Odd
The ratio of the probability of an occurrence of an event to that of nonoccurrence Any ratio of two natural numbers can be regarded as an odds:
Total: 50 Exposed: 20 Unexposed: 30 Odds of exposure: 20/50 divided by 30/50; or 20/30

Exposure odds
Ratio of those exposed to those who are not exposed

CCEB

Exposure Odds Ratio (OR)

D E E
a c

D
b d

Total a + b c + d

a/(a + c) /( ) a Odds1 = = c/(a + c) c b/(b + d) b Odds0 = = d/(b + d) d a/c ad OR = = b/d bc

CCEB

OR also sometimes called the cross-products ratio cross-

Cumulative Case-Control Design CaseMost familiar type of case-control design caseControls can be thought of as a sample of the source cohort who were diseasediseasefree at the end of follow-up (i.e., followsurvivors) survivors Called survivor sampling by some sampling authors
CCEB

What Measures Do We Need to Estimate an Exposure Odds Ratio for the Source Cohort?
Odds of EXPOSURE in diseased Odds of EXPOSURE in non-diseased non-

CCEB

Entire Source Cohort

DISEASE EXPOSED DISEASEFREE

Sample of p Source Cohort

EXPOSED

a c

b d

UNEXPOSED

C
N1

D
N0

UNEXPOSED

n1 n0 If cases are representative of diseased in source p p population, then a/c (exposure odds) , ( p ) estimates A/C If controls are representative of non-diseased in representative nonsource population at the end of follow-up, then b/d follow(exposure odds) estimates B/D

CCEB

Exposure Odds Ratio in a Case-Control Study CaseEXPOSURE odds in CASES = EXPOSURE odds in CONTROLS a c a b ad = = = b d c d bc

CCEB

Conditions
The exposure odds ratio is an estimate of the measure of association possible from a cohort study if the following f ll i conditions are met: diti t 1. Cases are representative of diseased in source 1 C t ti f di di cohort, then a/c (exposure odds) estimates A/C 2. Control are representative of disease-free in source diseasecohort, then b/d (exposure odds) estimates B/D cohort

CCEB

The Rare Disease Assumption

If you wish to use data from a cumulative case control design to estimate the cumulative incidence ratio (CIR) or incidence rate ratio (IRR), an additional condition must be met for the exposure odds ratio to estimate CIR or IRR: the disease must be rare Why?

CCEB

Odds
odds = probability / (1 probability) odds = risk / (1 risk) If risk << 1.0, then odds risk
Risk Odds 0.010 0 010 0.010 0.050 0 050 0.053 0.100 0 100 0.111 0.20 0 20 0.25 0.80 0 80 4.00

CCEB

Cumulative Case-Control Design Case-

The disease must be rare in order to estimate RR Assumes no differences in follow-up followrates among the exposed and unexposed Best it d f B t suited for a short latency period h tl t i d between exposure and outcome
E.g., acute epidemic setting E t id i tti

CCEB

 What if the disease outcome is not rare? What if there is a long latency period between exposure and outcome and differential follow up follow-up among patients? Wh t if you want to estimate the What tt ti t th incidence rates?
CCEB

Incidence Density Design for Casey g CaseControl Studies

Best for an identifiable source cohort in which follow-up time is highly variable followbetween persons (e.g., dynamic cohort) RareRare-disease assumption not needed Controls can be thought of as a random sample of the person-ti l f th person-time of the source f th cohort Called i k set C ll d risk set sampling by some authors t t li b th

CCEB

Cohort Study
persontime
26 14 17 26
NonNon random process

Exposed Unexpose d

26 22 24 20 26 26

CCEB

Study y population

Observation Period = Study outcome

UnDiseased diseased Exposed Unexposed d 2 3 3 2

PersonTime
26+17+26+24+26= 26 17 26 24 26

119

14+26+22+20+26=

108

Ratee = 2 119 = 0 0168 events/time units 0.0168 Rate = 3 108 = 0.0278 events/time units Rate Ratio = 0 0168 0 0278 = 0 60 0.0168 0.0278 0.60
CCEB

UnDiseased diseased Exposed Unexposed d 2 3 3 2

PersonTime
26+17+26+24+26= 26 17 26 24 26

119

14+26+22+20+26=

108

Rate Ratio = (2 / 119) (3 / 108); rearrangement (2 / 3) (119 / 108) = 0.60

CCEB
odds of exposure in diseased subjects

odds of exposure in underlying person-time

Entire Source Cohort

DiseaseDiseaseDisease Free Total Exposed Unexposed A C N1 B D N0 T1 T0 T PersonPersonTime Y1 Y0 Y

CCEB

Sample of Source Cohort

DiseaseDiseaseDisease Free Total Exposed Unexposed Samples of diseased and total person-time personat risk CCEB A C N1 B D N0 T1 T0 T PersonPersonTime Y1 Y0 Y

n1

The OR from incidence density sampling is incidence sampling equivalent to the rate ratio (no rare disease p ) assumption needed)
Incidence Rate of DISEASE in EXPOSED IRR= -----------------------------------------------------------------Incidence Rate of DISEASE in UNEXPOSED Exposed cases / Person-time (exposed) Person= -----------------------------------------------------------------Unexposed cases / Person-time (unexposed) PersonExposed cases / unexposed cases E d d = --------------------------------------------------------------------PersonPerson-time (exposed)/Person-time (unexposed) (exposed)/PersonExposure odds in DISEASED = --------------------------------------------------------------------------------------------------------------Exposure odds in Person-time (either in the entire cohort or a sample of the Personcohort)

CCEB

Entire Source Cohort

DiseasePersonTotal Time Disease Free Exposed Unexposed U d A C N1 B D N0 T1 T0 T Y1 Y0 Y

Sample of Source Cohort

CASES EXPOSED a CONTROLS b

UNEXPOSED

c n1

d n0

If cases are representative of diseased in source cohort, then a/c (exposure odds) , ( p ) estimates A/C If controls are representative of total personrepresentative persontime in source cohort, then b/d (exposure odds) estimates Y1/Y0

CCEB

How Do We Obtain a Representative Sample of Total Person-Time at Risk i th S Ri k in the Source Population? P l ti ?
Density sampling: Select one or more controls from sampling: remaining disease-free members of the source diseasecohort at the instantaneous time period in which instantaneous each case occurs

The probability of control selection is proportional to the person-time at risk person-

CCEB

Case-Control Study
controls sampled

NonNon random process

Exposed Unexpose d

CCEB

Study y population

Observation Period = Study outcome

Procedures for Incidence Rate Sampling R t S li

1. 1 2. 3. 4. Determine the date on which the first case occurred Identify all members of the cohort (including cases) who were diseasedisease-free on that date (called the "risk set") Randomly select one control (or more) from the risk set Repeat steps 1-3 for 2nd, 3rd, last case 11. 2. 3. Controls are matched to cases on follow-up (at-risk) time follow- (atA case is eligible to be a control for another case before it became a case Control selection for each case is done with replacement (i.e., a subject can be selected as a control for multiple cases

5. 5 Arrange cases & controls in a 2x2 table

CCEB

Case-Control Study
controls sampled
1 2 3 4
NonNon random process

2 3 86

Exposed 5 Unexpose 7 d 8 9 10 6

CCEB

Study y population

Observation Period = Study outcome

Random Control Selection, 3 per case

Case C 2 3 8 6 7 Potential P t ti l controls t l 1,3,4,5,6,7,8,9,10 1 3 4 5 6 7 8 9 10 1,4,5,6,7,8,9,10 1,4,5,6,7,9,10 1 4 6 9 10 1,4,5,7,9,10 1,4,5,9,10 p Exposure odds Sampled S l d controls 1,6,9 169 5,8,9 4,9,10 4 9 10 1,5,10 4,9,10 8/7

CCEB

Diseased Exposed p Unexposed 2 3

Rate

Sampled p persontime (controls) ( t l ) 8 7

Total PersonTime 119 108

IRR = (2 / 119) (3 / 108) = 0.60 = (2 / 3) (119 / 108) Equal (2 / 3) (8 / 7) = 0.58 ( ) ( ) e cep o except for
CCEB random variation

Notes on Incidence Density Design

Some selected controls may later be selected as cases, especially if incidence is high ! Some controls may be selected more than once ! Probability of a person being selected as a control is proportional to that persons contribution to the person denominator (i e total person-time at risk) of incidence (i.e., personrate calculations in the source cohort

CCEB

Notes on Incidence Density Design

No need for rare disease assumption if you use density sampling Also works if exposure status changes over time

CCEB

Biases in Case-control CaseStudies

Selection bias
Occurs when selection of either the cases or controls is related to the probability of exposure Typically occurs when controls not se ected o the source population selected from t e sou ce popu at o

Differential measurement of exposure between cases and controls

Typically occurs when measurement of p p exposure takes place after disease has occurred Not a concern in electronic medical d

CCEB

Take-Home Take Home Messages on CC study

Much more efficient than a cohort design, especially for rare outcomes Validity depends upon whether controls provide a clear view of population from which cases arise The OR from incidence density sampling is equivalent to the rate ratio (no rare disease assumption needed) d d)

CCEB

Choice of Design
Hybrid Design y g
Retrospective Cohort analysis

Nested case-control caseanalysis

CCEB

Laheij et al. JAMA. 2004;292:1955-1960

Example: Do Thiazides Prevent Femur Fracture?

How could this be studied as a RCT?

CCEB

A staggering amount of work; logistic and ethical difficulties

Thiazides
Random allocation

No thiazides

Study y population CCEB

Observation Period = Femur fracture

Rate R ti R t Ratio = E Events / person-time i t t d t ti in treated Events / person-time in untreated

CCEB

Do Thiazides Prevent Femur Fractures?

How could this be studied as a cohort study?
System in Netherlands S i N h l d contains pre-existing drug & p g g diagnosis info for 108k people age 45
CCEB

Compile exposure, outcome, & confounder info on 108,000 subjects

NonNon Random process

Thiazide s No thiazides

Study y population= CCEB 108,000 people

Observation Period = Femur fracture

Rate R ti R t Ratio = E Events / person-time i t t d t ti in treated Events / person-time in untreated

CCEB

Do Thiazides Prevent Femur Fractures?

How could this be studied as a case-control study?
(Herings RMC et al J Clin Epidemiol RMC, al. 1996;49:115-119)

CCEB

Get outcome info on 108,000 subjects. Get exposure & confounder i f on 386 cases + Controls f d info 386 controls. sampled

NonNon Random process

Thiazide s No thiazides

Study y population= CCEB 108,000 people

Observation Period = Femur fracture

Data from Herings RMC, J Clin Epidemiol 1996;49:115-19 Cli E id i l 1996 49 115 19
femur fracture no femur fracture

CCEB

(cases) (controls) thiazides 46 70 116 no thiazides 340 316 656 total 386 386 772 Odds ratio = (46 / 340) (70 / 316) Or, to make math easier, (46 316) / (70 340) = 0.6 = unbiased estimate of rate ratio The rate of femur fracture is 40% lower in thiazide users than non-users (assuming no confounding).

total

They studied 772 y people instead of 108,000!

CCEB

Pharmacoepidemiology Part II at
Caveats and Pitf ll C t d Pitfalls

Yu-Xiao Yang, MD, MSCE, FACP

Center for Clinical Epidemiology and Biostatistics University of Pennsylvania School of Medicine

CCEB

Outline
Bias Confounding o eg s /be e t at o How to weigh risk/benefit ratio

CCEB

Bias often Encountered in Pharmacoepidemiology

Selection bias Misclassification bias otopat c b as Protopathic bias Immortal time bias

CCEB

Selection Bias
A distortion in the estimate of occurrence or effect resulting from the manner in which subjects are selected for the study

CCEB

Study question:
Does therapy with 6MP increase the risk of l k i k f leukopenia? i ?

CCEB

Design
Cohort study of IBD patients treated with 6MP compared to IBD patients not ith dt ti t t treated with 6MP S Setting: Health plan participants with 6MP

CCEB

Which 6MP treated patients should y you include?

At the start of the available data some data, patients are already taking 6MP Additional patients start taking 6MP during follow-up in the available data Other patients never take 6MP ne er

CCEB

Depletion of Susceptible p p Subjects

Treatment with mercaptopurine (6MP) can result in bone marrow suppression lt i b i
Rapid metabolism to 6TGN
1 i 300 people with genetic b i f very l in l ith ti basis for low TPMT activity Early severe leukopenia when treated with 6MP

Other reasons such as infection or drug interaction

Occur at any time while taking 6MP

CCEB

Depletion of Susceptible p p Subjects

If you include the prevalent users (those t ki (th taking 6MP at the start of the t th t t f th data), you will have selected a cohort of survivors
Those with early leukopenia will have been excluded Results will be biased toward ___________

CCEB

Depletion of Susceptible p p Subjects

If you include the prevalent users (those taking 6MP at the start of the data), you will have selected a cohort of survivors
Those with early leukopenia will have been excluded R Results will be biased toward the null lt ill b bi dt d th ll (could be away from the null in a different scenario) )

This problem is called Depletion of susceptibles a type of selection bias

CCEB

What is the solution to this problem?

CCEB

New Users Approach

By creating the study cohort exclusively of new users, d l ti of l i l f depletion f susceptible subjects can be avoided. O example Our
New users of 6MP compared to non-users of 6MP f

CCEB

Misclassification
Exposure misclassification Outcome misclassification Differential vs. non-differential vs non differential misclassification

CCEB

What does it mean to be exposed?

Complex exposure patterns
Episodic, continuous, remote, recent, current

Actual consumption vs. prescription Date prescribed date exposure started p p Days supplied duration of exposure
How to handle overlapping dispensing periods?

Plausible latency period between exposure and outcome Availability of OTC exposure
Example: Aspirin/NSAIDs

CCEB

Example
Statin use may reduce the risk of colorectal cancer l t l Primary definitions of statin exposure in published studies
Any prescription of statin within the past 12 month th Cumulative duration of statin use >5 years

CCEB

Defining Outcomes/Cases
Rule-out diagnosis vs. actual diagnosis Prevalent vs. incident diagnosis

CCEB

Lewis et al. PDS 2005;14:443

Defining Outcomes
Validity of the diagnosis
Direct validation (paper record review, physician or patient survey, etc.) C Corroborative procedures/treatment b ti d /t t t
Example: colon cancer, colorectal surgery, chemo

CCEB

Information / Misclassification Bias

Misclassification of disease or exposure status t t If misclassification is differential (i.e., differs between cases and controls), ff ) bias may be toward or away from the null value

CCEB

A Caveat about Non-differential Misclassification Bias

True or false
Non-differential bias should always bias the results towards the null
False False.

CCEB

A Caveat about Non-differential Misclassification Bias

The real answer is it depends Conditions when the statement is always true
The exposure is binary
Other conditions required if it is >2 levels

Exposure misclassification errors are independent of errors in other variables in the analysis
E.g., one measure from a comprehensive questionnaire

Ab Absence of i t f interactions with other sources of ti ith th f systematic error, e.g., selection bias and g confounding CCEB

A Caveat about Non-differential Misclassification Bias

A th caveat Another t
Bias towards the null does not always lead to an underestimate of the relative risk The rules refer to expected values, ie., the average result of applying estimator to repeated samplesnot to the value estimated from a specific study
Definition of non-differential: the probably of error is the same between those with the outcome and those w/o the outcome

It probably is incorrect to claim (as authors often do) that the estimate from a study must be an underestimate because the bias is towards the null.
Probably better to say the estimate is more likely to be below the true estimate than above it

CCEB

Difference in life expectancy: 79.7 vs. 75.8 years; P = 0.003 r 0 003 28% Reduction in risk of death per year!!

CCEB

Redelmeier et al. Ann Intern Med. 2001:134:955-962

Immortal Time Bias

F/u time Oscar Winners Immortal Time Birth Bi th Winning Oscar Death

F/u time NonNon i N -winners

CCEB

Birth

Death

Long-term infliximab treatment is Safe?

F/u time Exposed Immortal Time 1994 or CD dx date Unexposed F/u period 1994 or CD dx date Death HR for mortality: 1.33 (95% CI, 0.56 to 3.00) Start of Infliximab F/u period Death F/u time

CCEB

Fidder et al. Gut 2009;58:5018

Immortal Time Bias

How to account for it?
Treat exposure as time-dependent In Cox g regression
Unexposed Period Exposed period

Time

Immortal Time Enrolment date Drug Exposure

F/u period Censoring event

CCEB

Ann Intern Med. 2006;145:361-363

CCEB

Long-term infliximab treatment is Safe?

F/u time Exposed Immortal Time 1994 or CD dx date Unexposed F/u period 1994 or CD dx date Death HR for mortality: 2.37 (95% CI, 1.02 to 5.33) Start of Infliximab F/u period Death F/u time

CCEB

Lewis JD Gut 2010;59:1586-1587

Statin Use and Lung Cancer

Study cohort: 483,733 VA patients Study period: Oct 1998 to June 2004 Study design: Case-control Exposure
Cases: Any Rx for statin prior to the dx of lung CA C t l A R f statin prior t th end of Controls: Any Rx for t ti i to the d f observation period

Results: Statin associated with 45% reduction in lung cancer risk (adjusted OR 0.55, 95% CI: 0.52-0.59). CCEB
Khurana et al. Chest. 2007;131:12821288

Time-Window Bias in Case-Control St di C C t l Studies

Cases had a shorter observational period than controls Shorter observational period = less chance for (statin) ( t ti ) exposure Over-representation of unexposed cases = spurious appearance of benefit of the drug (statin)

CCEB

Time-Window Time Window Bias

How to address this bias?
Use a cohort design with time-varying exposure U i id Use incidence density sampling to select d it li t l t controls
Select one or more controls from remaining disease diseasefree members of the source cohort at the instantaneous time period in which each case occurs The probability of control selection is proportional to the person-time at risk

CCEB

Time-Window Time Window Bias

Statin use and lung cancer: A GPRD study

CCEB

Suissa et al. Epidemiology 2011;22: 228231

PPI Therapy and Colorectal py Cancer

Potential mechanism
PPI-induced hypochlorhydria

Secondary hypergastrinemia g

How would you investigate this potential association?

Increased cell proliferation p

Accelerated progression through the adenomacarcinoma sequence

Increased colon cancer risk

CCEB

PPI and Colorectal Cancer

RCT? Prospective Cohort? Nested case-control?
Most feasible Design Can use large electronic medical records (e.g., THIN) ) Identify incident gastric cancer and select controls using incidence density sampling How to define exposure?
PPI exposure before index date

CCEB

PPI and Colorectal Cancer

Potential problem in exposure definition d fi iti
Patients with colorectal cancer may have non-specific non specific GI symptoms before the caner dx Empirical PPI therapy is often prescribed for empirical treatment of such symptoms PPI use close to cancer dx date (index ( date) might appear to cause colorectal cancer CCEB

PPI Therapy and Colorectal Cancer

Duration of Controls N Crude OR (95% Cases N (%) PPI (%) CI) NonNon-users 3,663 (82.7) 39,159 (88.4) Reference < 1 year Recent 400 (9.0) 1,663 (3.8) 2.6 (2.3-2.9) (2.3Past 211 (4.8) 2,017 (4.6) 1.1 (1.0-1.3) (1.01-2 years 67 (1.51) (1 51) 573 (1.3) (1 3) 1.3 (1.0-1 6) 1 3 (1.0-1.6) (1 0 2-3 years 34 (0.8) 385 (0.9) 1.0 (0.7-1.4) (0.73-4 years 24 (0.5) 211 (0.5) 1.2 (0.8-1.9) (0.84-5 years 17 (0.4) 140 (0.3) 1.3 (0.8-2.2) (0.8>5 years 16 (0.4) 144 (0.3) 1.2 (0.7-2.0) (0.7-

Adjusted OR (95% CI) Reference 2.6 (2.3-2.9) (2.31.1 (0.9-1.3) (0.91.2 (0.9-1.6) 1 2 (0.9-1 6) (0 9 0.9 (0.6-1.3) (0.61.1 (0.7-1.7) (0.71.1 (0.7-1.9) (0.71.1 (0.7-1.9) (0.7-

Protopathic bias? p

CCEB

Yang et al. Gastroenterology 2007;133:748754

Protopathic bias
Use of the drug to treat early signs of the t th outcome
Early symptoms of CRC leading to PPI use

Different from confounding by indication

Why? Because the indication here is the outcome!

CCEB

Protopathic Bias
How to address it?
Lag-time approach: a specific time period before the date of diagnosis with the disease under study would be excluded from the exposure assessment But what is the optimal lag-time? 6 p g months? 12 months? Should it be dependent on the outcome?

CCEB

Statistical Method to Estimate Lag-Time

Step 1: Estimate a series of ORs assuming increasing laglag time (generally in monthly increments). Step 2: U S 2 Use segmental regression analysis to estimate optimal l i l i i i l lag-time
y = a + bx + cx2 if x < x0 y = plateau (constant) if xx0
x= lag time; x0 = change point y=ln(OR) l (OR)

CCEB

Tamim et al. PDS 2007; 16: 250258

Confounding in Pharmacoepidemiology
Confounding by indication
Examples Measures to address confounding by indication i di ti Channeling

CCEB

 Confounding may be considered to be a mixture of effects. Specifically, the i t f ff t S ifi ll th estimate of the effect of the exposure of interest is distorted because it is mixed with the effect of an extraneous factor.
(Rothman)

CCEB

Confounding of an g Association
Confounder

Medication

Outcome

CCEB

CCEB

Causal Pathway
Factors in the causal pathway are not confounders (more on this later) f d ( thi l t )

Medication

Causal pathway

Outcome

CCEB

PPI Therapy & Fractures py

Possible mechanisms
Osteoclastic PP inhibition may decrease bone resorption Acid suppression may decrease Ca absorption Gastrin may induce parathyroid hyperplasia PPI-induced B12-insufficiency PPIB12 Low B12 is associated with decreased bone formation Homocysteinemia can weaken collagen cross-linking* cross Increased fall risk*

*Mechanisms not associated with changes in bone mineral density Mechanisms

CCEB

Study Question
Is PPI therapy a risk factor for hip fractures? f t ? Ways to do the study
RCT
May be unethical to randomize

Cohort study - OK Case-control study - OK Case-

CCEB

CCEB

 Design

Methods M th d

Nested case-control study

General Practice Research Database (GPRD)

Electronic medical records system 1987-2003 (n=9,371,083)

Eligible Cohort (n=1 816 417 ) (n=1,816,417

>50 years of age at enrollment and >1 year of follow-up

Cases
Incident hip fracture cases

Controls
Incidence density sampling Matched on sex, index date, year of birth, date of the beginning of UTS follow-up and d b i i f f ll d duration of UTS follow-up ti f f ll before index date

CCEB

PPI Therapy & Hip Fractures

Unadjusted OR ( (95%CI) ) No acid suppressive therapy > 1 yr OBSERVED PPI Therapy reference 1.8 (1.7(1.7-2.0) Adjusted OR Adj t d (95% CI) reference 1.4 (1.3(1.3-1.6)

Yang et al. JAMA 2006;296:2947 2953 al 2006;296:2947-2953

CCEB

PPI Therapy & Hip Fractures

Cumulative PPI Adjusted Odds j therapy durations Ratio (95% CI)

PPI non-users 1 year 2 years 3 years

4 years

Reference 1.22 (1.15-1.30) 1.41 (1.28-1.56) 1.54 (1.37-1.73) 1.59 (1.39-1.80)

CCEB

Yang et al. JAMA 2006;296:2947-2953

Effect of Dosage
>1 yr H2RA Average Daily dose >1 yr PPI Average Daily dose QD 1.4 (1.3-1.5) (1.3BID 2.7 (1.8-3.9) (1.8-

QD Adjusted OR (95% CI) 1.2 (1.1(1.1-1.4)

BID 1.3 (1.2-1.5) (1.2-

Low

High g Acid Suppression

Yang et al. JAMA 2006;296:2947-2953

CCEB

PPI Therapy and Fracture Risk

Targownik et al.

CMAJ
2008;179(4):319-26

CCEB

Is this a real biological g effect?

Confounding? C f di ?
Doctors may be more likely to prescribe PPI therapy in patients who are older, frail, older frail demented or with poor nutritional status than healthier patients p These comorbid conditions are associated with increased facture risk How will we know whether the increased risk of hip fracture among PPI users was due to the PPIs or the reason for receiving PPI therapy? Answer: Must control for confounding CCEB

Options for Controlling Confounding in Observational Studies

Design stage
Matching Restriction

Analysis stage
Stratified analyses y Mathematical modeling

CCEB

PPI Therapy and Risk of py Fractures

Objective: to estimate the PPI fracture Objective: association in patients without major i ti i ti t ith t j risk factors for fracture C CaseCase-control study # : to identify #1: #1 f major risk factors for hip fracture Case-control study #2: reassess the Case#2: association among patients without major risk factors j i kf t
Jick et al. Pharmacotherapy 2008;28(8):951959 2008;28(8):951

CCEB

PPI Therapy and Risk of py Fractures

M t common RF id tifi d in Phase 1 Most RFs identified i Ph
Previous fractures B12 Deficiency Osteoporosis CVA Accidental Falls Seizures FeFe-deficiency anemia

Patients with these diagnoses were excluded in Phase 2

CCEB

Jick et al. Pharmacotherapy 2008;28(8):951959 2008;28(8):951

PPI Therapy and Fractures

Conclusion PPI therapy is not associated with hip fracture risk in patients without major RFs for fractures

CCEB

Jick et al. Pharmacotherapy 2008;28(8):951959 2008;28(8):951

CCEB

How to interpret these data?

Previously observed positive association was due to residual confounding Effect modification according to fracture risk
Threshold phenomenon between BMD and fracture

Generalizability
80% of hip fractures excluded

Restriction based on intermediate factors between PPI and fracture

Osteoporosis, B-12 deficiency, previous fractures, Betc.

CCEB

Use of Restriction Analysis to Control for Confounding

Confounder C f d
Used to restrict cohort

PPI

Intermediate
Osteoporosis, B-12 deficiency, etc B-

Will bias towards the null Generally NOT used to restrict cohort

CCEB

Hip Fracture Hi F t

Mathematical Modeling
Mantel Haenszel methods Logistic regression Linear regression Cox proportional hazard regression Etc.
CCEB

Potential Confounders Considered

Demographics & Oth Healthcare Info. D hi Other H lth I f
Age at enrollment Sex Body mass index Smoking history Excessive ETOH Calendar year of enrollment D Duration of f ll ti f follow-up Number of prior visits

CCEB

Potential Confounders Considered

Diagnoses
Congestive hear failure Cerebral vascular accident Dementia Impaired mobility Myocardial infarction COPD or Asthma Peptic ulcer disease Peripheral vascular disease Rheumatoid arthritis Vision loss Celiac sprue Pagets disease Osteomalasia Chronic renal failure Cushings disease Inflammatory bo e d sease a ato y bowel disease Menopausal status Prior history of fracture Seizure disorder

CCEB

Potential Confounders Considered

Drugs
Axiolytics Antidepressants Anti-Parkinson's Thiazide diuretics Corticosteroids Bisphonsphonate Calcitonin Anticonvulsants Thyroxine Calcium supplementation Vitamin D supplementation

CCEB

 What do the results of a multivariable model mean? It is a measure of the association of each variable with the outcome of interest after adjusting for all other variables in the model i bl i th d l
CCEB

Pitfalls of Modeling
Ignoring the stratified results
Co-linear variables Co Absence of overlap

Too many variables Adjusting for variables in the causal pathway Adjusting for variables that are not confounders
CCEB

Pitfalls of Modeling
Assuming that modeling can correct problems with the data t bl ith th d t collection
You cant turn garbage into gold with statistics

Residual confounding when gradation of disease severity not captured

CCEB

Other Potential Solutions

Statistical methods have been developed to t combine multiple variables into a bi lti l i bl i t single variable
P Propensity scores it Risk scores C Comorbidity indices bidi i di
Charlson / Deyo Score

CCEB

What is a Propensity Score?

Variable which describes the probability of receiving a given treatment conditioned on a set of covariates U t diti Use traditional modeling techniques to l d li t h i t create propensity score
Dependent variable treatment Independent variable any variable other than the outcome Propensity score corresponds to the probably of receiving the treatment Eith match or stratify subjects by the Either t h t tif bj t b th propensity score

CCEB CCEB

Channeling
What is channeling?
Definition: Drugs with similar therapeutic indications are prescribed to groups of patients with prognostic differences Can lead to confounding by indication

CCEB

Channeling
A study comparing patients started on COX-2 inhibitors after their initial marketing vs. those remaining on NSAIDs in 1998-1999

Wolfe F et al. J Rheumatol 2002;29:101522

CCEB

How to Deal with Channeling?

Approach similar to whats used for confounding by indication f di b i di ti Propensity score matching or adjusting The goal is to even out the probability of receiving the drug Limitations
Large sample size required Unmeasured factors cannot be accounted for CCEB

Risk versus Benefit

All drugs can cause adverse events Must weigh risks vs potential benefits s tolerance s pat e t and physician Risk to e a ce is patient a d p ys c a specific
Frequency of event q y Severity of outcome Reversibility e e s b ty Alternative therapies Personal preference CCEB

CCEB

Hazards of Common Professions

Occupation Risk of Death per 100,000 100 000 person years 0.4 04

Office work

Firefighter

10.6

Taxi driver CCEB Cohen JT. Health Affairs 2007:26:636-46 2007:26:636-

36.1

Hazards of Common Medications

Medication Aspirin to prevent heart disease and cancer 50 year old men Natalizumab for MS Rofecoxib for arthritis pain
Cohen JT. Health Aff i 2007:26:636C h JT H lth Affairs 2007:26:636-46 2007 26 636

Risk of Death per 100,000 100 000 person years 10.4 65 76

CCEB

Hazards of Modes of Transportation

Transportation Risk of Death per 100,000 100 000 person years 0.15 0 15 11 1.3 450

Commercial plane Car Additional risk from talking on cell phone Motorcycle CCEB Cohen JT. Health Affairs 2007:26:636-46 2007:26:636-

Studies Lead to Withdrawal of Drug for Bowel Ailment

I cant believe the F.D.A. would do such a thing. Why are they being so cruel? asked Lori Egan cruel? Egan, 39, of Fredericksburg, Va. I would rather take my chances of having a heart attack than live in I.B.S. hell. ---(March 30, 2007)

CCEB

Conclusions
All drugs can cause adverse reactions d d ti Observational drug surveillance studies have an important role in assessing safety of medications The validity of observational drug surveillance studies depends on
Appropriate choice of study design Appropriate definition of exposure and outcome Addressing potential biases and confounding

A Acceptability of risk depends on potential t bilit f i k d d t ti l benefits, alternative therapies, patient tolerance CCEB

Questions?

CCEB