Pharmacoepidemiology Part 3 at

Studies Using Automated Databases g

Yu-Xiao Yang, MD, MSCE, FACP Yang MD MSCE

Center for Clinical Epidemiology and Biostatistics University of Pennsylvania School f Medicine S h l of M di i

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Pharmacoepidemiology Observational Studies

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

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Data Source
Characteristics of an ideal electronic data source:
Inpatient, outpatient emergency care p , p g y records Behavioral factors (smoking, ETOH) Anthropometry data (height weight) (height, All laboratory (including pathology) and radiology tests gy All prescribed and OTC medications All components of data linkable L Large # of patients who are populationf ti t h l ti representative Paper chart review possible p p CCEB

Automated Databases in Pharmacoepidemiology

Existed since 1980 in North America Major reasons to use them
Efficient Inexpensive Large sample size Obviates recall bias

Not good for g

Illnesses that do not come to medical attention Illnesses that are poorly defined by diagnostic g y (e.g., S J Syndrome) ) coding systems ( g , Steven-Johnson Sy Inpatient drug exposure (not included in some) Delayed drug exposure (patient may lost eligibility) Some confounder info critical (e g smoking) (e.g., Interested in Rx drugs not covered or OTC drugs

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Automated Database Available in US

Pharmacoepidemiology Databases
Claims Databases M di l Record Databases Medical R dD t b In-between claims and medical record

Essential data elements

Prescription information Medical Diagnoses (included or linkable)

Missing or incomplete data elements

OTC medication (generally not available) Smoking ETOH BMI (either incomplete or not Smoking, ETOH, available) Laboratory and radiology data (incomplete) I Inpatient/ER records ( t available for some) ti t/ER d (not il bl f )

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Claims Database
Examples of Claims Databases
Medicaid
Joint state and federal funding that provide medical and prescription coverage to lowincome individuals

Medicare data
Anyone >65 years is eligible

Pennsylvania Pharmaceutical Assistance Contract for the Elderly Data (State of Pennsylvania)
Offers prescription subsidy to low-income Pennsylvania residents Medicareeligible but not poor enough to get Medicaid prescription coverage

Major advantages
Ability to link diagnosis information with p y g prescription data p Financial incentive means near complete prescription information

Major limitations: j
Limited generalizability Lack of behavioral and anthropometry data Questionable validity of diagnoses Limited number of drug categories and drugs covered OTC medication information missing

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Example using Medicaid/Medicare Data

Study question: is cisapride use associated ventricular arrhythmia? Study Design: Nested case-control Study population: Medicaid enrollees Cases: Patients with sudden cardiac death or ventricular arrhythmia Controls: Selected using incidence density sampling matched on eligible at-risk time before index date Exposure: cisapride prescription obtained from prescription coverage linked with Medicaid Statistical analysis: conditional logistic regression

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Hennessy et al. Br J Clin Pharmacol 2008;66:375385

Cisapride and Ventricular Arrhythmia

Hennessy et al Br J Clin Pharmacol 2008;66:375385 al.

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Antihypertensives and Fracture Risk

Study question: are antiHTN meds associated osteoporotic fracture risk? Study Design: Retrospective cohort study Study population: Patients enrolled in Medicare and PACE Exposure: Various classes of antiHTNs Outcome: Incident osteoporotic fractures Statistical analysis: Cox proportional hazard regression model
Solomon et al. JBMR 2011;26:15611567

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Antihypertensives and Fracture Risk

Solomon DH et al. JBMR 2011;26:15611567

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Medical Records Databases

Examples of Medical Record Databases
Local
University of Pennsylvania Health System (EPIC) Geisinger Health System

Nation-wide
General Practice Research Database (GPRD) The Health Improvement Network (THIN)

Advantages
Diagnoses can be validated easily (e.g., pathology) S Some b h i behavioral and anthropometry data available l d th t d t il bl

Disadvantages
Local records may not have sufficient sample size Local databases are hard to query for research BMI and smoking information are often incomplete OTC Rx use information incomplete or missing R i f ti i l t i i Costly computer hardware/software needed for GPRD

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Example using UPHS Local data

Study question: Is insulin therapy associated prevalent colorectal adenoma risk? Study Design: Cross-sectional study Study population: Patients undergoing screening colonoscopies at UPHS Cases: Patient with at least 1 adenoma found Controls: Patient without adenoma Exposure: Prior insulin use Statistical analysis: Multivariable logistic regression
Wong et al. Manuscript under review

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Insulin Therapy and Colorectal Adenoma

Any adenoma
Exposure definitions Duration of insulin exposure Case Control Crude OR Adjusted OR

Advanced adenoma
Case Control Crude OR Adjusted OR

6 months[WH1]

49 (26%) ( ) 41 (23%) 40 (22%) 34 (19%) 23 (14%)

144 (22%) ( ) 124 (19%) 92 (15%) 77 (13%) 43 (8%)

1.2 ( (0.9-1.8) ) 1.2 (0.8-1.8) 1.6 (1.1-2.4) 1.6 16 (1.0-2.5) 2.0 (1.1-3.4) (1 1 3 4)

1.3 ( (0.9-1.8) ) 1.2 (0.8-1.8) 1.6 (1.1-2.5) 1.7 17 (1.1-2.6) 2.0 (1.2-3.4) (1 2 3 4)

14 (24%) ( ) 10 (19%) 9 (17%) 8 (15%) 6 (12%)

144 (22%) ( ) 124 (19%) 92 (15%) 77 (13%) 43 (8%)

1.1 ( (0.6-2.1) ) 0.9 (0.5-1.9) 1.2 (0.5-2.4) 1.2 12 (0.6-2.7) 1.6 (0.7-4.1) (0 7 4 1)

1.2 (0.6-2.2) ( ) 0.9 (0.5-2.0) 1.2 (0.6-2.5) 1.3 13 (0.6-2.9) 1.7 (0.7-4.3) (0 7 4 3)

12 months[WH2]

18 months

2 years

3 years

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[WH1]I [WH2]I

assume the reference group is no insulin use. Exclude those with <6m insulin users. assume this is the same model as Table 2.

PPI Therapy and CAP

Potential Mechanisms
Increased bacterial colonization with acid suppression Direct immunosuppressive effect of PPI

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Example using GPRD

Study question: Is PPI therapy associated the risk of community-acquired pneumonia (CAP)? Study Design: Nested case-control study Study population: Adult GPRD population (19872002) Cases: Patient incident CAP Controls: selected using incidence density

sampling, matching on practice site, calendar period, period and follow up duration follow-up duration.
Exposure: Prior PPI exposure Statistical analysis: Conditional logistic CCEB regression

Data Source
General Practice Research Database (GPRD)
Containing information on over 8 million patients followed by GPs Patients are representative of the national population l ti Dx and Rx data are accurate and complete Used in a variety of clinical studies

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PPI Therapy and CAP

Type of PPI Cases exposure p N (%) NonNon-use Current use Past use P Controls N (%) SexSex- and AgeAgeadjusted OR j (95% CI) Adjusted OR (95% CI) Reference 1.02 (0.97-1.08) (0.970.95 (0.90-1 0) 0 95 (0.90-1.0) (0 90 73,187 (91.4) 770,626 (96.3) Reference 3,455 (4.3) 3,424 (4.3) 3 424 (4 3) 10,031 (1.3) 19,215 (2.4) 19 215 (2 4) 2.05 (1.96-2.15) (1.961.50 (1.44-1 56) 1 50 (1.44-1.56) (1 44

*Adjusted for t hi f t *Adj t d f matching factors (practice site, calendar year and duration of follow-up ) sex, age at ti it l d d d ti f f ll ), t index date, current smoking, alcoholism, total number of GP visits during the past year, total number of hospitalizations during past year, CAP prior to GPRD enrollment, chronic obstructive pulmonary disease or asthma, myocardial infarction, congestive heart failure, chronic renal failure, cirrhosis, , y , g , , , diabetes mellitus, stroke, any malignancies other than basal cell skin cancer and dementia, as well as histamine type 2 receptor antagonist, anxiolytic, antidepressant, anti-parkinsonian drug, antipsychotic, barbiturate, opiate, corticosteroid, antibiotic and non-steroidal anti-inflammatory drug use.

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Sarkar et al. Annals of Internal Medicine. 2008;149:391-8.

PPI Therapy and CAP

Type of PPI exposure NonNon-use Adjusted OR (95% CI) Reference

Among current users

Daily dose 1.5 DDD/day >1.5 DDD/day Duration of use before index date <30days New starters Others 3030-180 days >180 days 1.00 (0.95-1.06) (0.951.23 (1.05-1 45) 1 23 (1.05-1.45) (1 05 1.74 (1.49-2.03) (1.492.45 (2.04-2.95) (2.040.91 (0.69-1.19) (0.691.09 (0.98-1 22) 1 09 (0.98-1.22) (0 98 980.91 (0.84-0.97) (0.84-

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Sarkar et al. Annals of Internal Medicine. 2008;149:391-8.

PPI Therapy and CAP

Type of PPI exposure Non use Non-use H2RA new starters Within 14 days before index date Within 7 days before index date Within 2 days before index date PPI new starters Within 14 days before index date Within 7 days before index date Within 2 days before index date Adjusted OR (95% CI) Reference 3.90 (3.18-4.78) (3.185.21 (4.00-6.80) (4.007.66 (5.19-11.31) (5.193.16 (2.45-4.08) (2.453.80 (2.70-5.41) (2.706.53 (3.95-10.80) (3.95-

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Sarkar et al. Annals of Internal Medicine. 2008;149:391-8.

Data Source
Combined claims and medical record databases
Kaiser Permanente Medical care program Group Health (HMO)

Advantages
Large size, representative population size Stable membership Comprehensive clinical and pharmacy information linked electronically Outcome validation possible

W k Weaknesses
Lack racial or socioeconomic information Somewhat restrictive drug formularies

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A Study Using KP Data

Study question: Is pioglitazone use associated the risk of bladder cancer? Study Design: Retrospective cohort study Study population: KPNC enrollee > 40 years with diabetes mellitus Exposure: pioglitazone based on KPNC pharmacy database Outcome: bladder cancer in KPNC cancer registry Covariates: Smoking information obtained from patient telephone interview Statistical analysis: Cox regression y g CCEB
Lewis JD et al. Diabetes Care 2011;34:916922

Pioglitazone and Bladder Cancer

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Lewis JD et al. Diabetes Care 2011;34:916922

A Study using Group Health

Study question: Is PPI therapy associated the risk of community-acquired pneumonia (CAP)? Study Design: Nested case-control study Study population: Group Health enrollees > 65 yrs Cases: Patient incident CAP by x-ray or trating physician assessment Controls: selected using incidence density sampling, matching on age, sex and calendar year li t hi d l d Exposure: current PPI exposure based on computerized pharmacy records Statistical analysis: Conditional logistic regression CCEB
Dublin et al. Pharmacoepidemiol Drug Saf. 2010;19(8): 792802

PPI Therapy and CAP

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Dublin et al. Pharmacoepidemiol Drug Saf. 2010;19(8): 792802

Choice of Data Source

Logistical issues
Local collaboration generally necessary
Kaiser Permanente Group Health p Local Medical Records Database

Open but regulated access

CMS data GPRD (www.gprd.com) THIN (administered by EPIC www.epic-uk.org) PACE (maybe) ( y )

Data-specific considerations
Nature of outcome or exposure (e.g., histologic diagnosis) Healthcare system (e g Implementation of screening (e.g., guidelines) Time periods of data (availability of OTC drugs) Possibility of data validation y Availability of relevant data (e.g., smoking, alcohol, BMI)

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Summary
There is no single ideal database Each has its advantages and disadvantages
Validity of diagnosis is generally better in medical records database than claims database Claims database can provide excellent prescription medication information

Each has proven it can be useful for pharmacoepidemiology research Appropriate choice depends on the study question CCEB

The Steps

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