# Presentation: 673692

## ADHD drugs and CV outcomes: Preliminary feasibility study results

- David J. Graham, MD, MPH
- on behalf of the FDA
- Epidemiology Contracts Study Team
- DSARM Advisory Committee Meeting
- February 9, 2006

## FDA’s Epidemiology Contracts Program

- Replaces Cooperative Agreement Program
- Provides capability to study safety questions in a population setting and to collaborate with non-govt experts
- 4 awardees				   _Covered lives_
- HMO Research Network		       3.2 million
- Ingenix (i3 Drug Safety)		        12 million
- Kaiser Permanente Research Institute       6.1 million
- TN and WA Medicaid		       2.2 million
- Turnover: 1 yr: 8%-30%; 5 yrs: 25%-80%
- Funding
- 2005-06		$1.6 million
- 2006-07		$0.9 million

## Feasibility study design

- Inception cohorts, all ages
- Study period
- Jan 1998-June 2005 (i3, KPRI, Medicaid)
- July 2000-June 2005 (HMO RN)
- Drugs of interest
- Amphetamine or dextroamphetamine
- Methylphenidate
- Atomoxetine
- Age-groups
- Children/adolescents (1-19 years)
- Adults (20-64 years)
- Outcomes of interest
- Sudden unexplained death
- Acute myocardial infarction
- Other ischemic heart disease
- Cerebrovascular accident
- Arrhythmia
- Hypertension
- Pulmonary hypertension

## Base population characteristics over study period

## Number of patients treated with ADHD drugs by age-group

## Person-years (crude) of ADHD drug use by age-group

## ADHD drug use (% males) by age-group

## Persistency of ADHD drug use by drug in 0-19 year olds

**Methylphenidate**  

**Amphetamine**  

**Atomoxetine**  

## Persistency of ADHD drug use by drug in 20+ year olds

**Methylphenidate**  

**Amphetamine**  

**Atomoxetine**  

## Cardiovascular outcomes of interest:Estimated population background rates

- Sudden unexplained death
- Children/adolescents: 1-9 per 105 pyrs
- Adults: Age 20-64:  45 per 105 pyrs
-             Age 65+:  700 per 105 pyrs
- Acute myocardial infarction
- Children/adolescents:  10-20 per 105 pyrs
- Adults:  Age 20-64:  200 per 105 pyrs
-              Age 65+:  1700 per 105 pyrs
- Stroke (all types)
- Children/adolescents:  3 per 105 pyrs
- Adults:  Age 20-64:  150 per 105 pyrs
-              Age 65+:  1200 per 105 pyrs

- Sources: Heart disease and stroke statistics-
- 2004 update.  American Heart Association;
- US census data, 2000

## Counts of potential study outcomes within inception cohorts,based on 1 hospital discharge diagnoses

- AMI: acute myocardial infarction
- IHD: ischemic heart diseas
- CVA: cerebrovascular accident (stroke)
- HTN: hypertension

## All cause mortality reported within inception cohorts

-   Deaths occurred at any time after cohort entry
-   From any cause
-   In-hospital only from 2 sites, not reported from 1 site
-   Sudden out of hospital deaths included from 1 site
- 2 sites have death certificate linkage; SCD validated at 1
- NDI search required with other 2 sites - turnover, time, $$
-   Total deaths substantially underestimated

## Crude frequency of diagnoses that could increase the risk of cardiovascular outcomes in ADHD drug treated patients

## Power to identify a given risk ratio with abackground rate = 15 per 105 person-years(AMI in children 1-19 years)

**Power (1-beta)**

**Exposure cohort person-years (thousands****)**

-  40

-  80

- 120

- 160

- 200

- 240

- 280

- 320

-  360

- 400

- 0.00

- 0.20

- 0.40

- 0.60

- 0.80

- 1.00

**RR=2**

**RR=3**

**RR=5**

## Power to identify a given risk ratio with abackground rate = 3 per 105 person-years(CVA in children 1-19 years)

**Power (1-beta)**

**Exposure cohort person-years (thousands)**

- 40

- 80

- 120

- 160

- 200

- 240

- 280

- 320

- 360

- 400

- 0.00

- 0.20

- 0.40

- 0.60

- 0.80

- 1.00

**RR=2**

**RR=3**

**RR=5**

**RR=10**

## Power to identify a given risk ratio with a

**Power (1-beta)**

**Exposed cohort person-years (thousands**)

-  0

- 20

- 40

- 60

- 80

- 100

- 0.00

- 0.20

- 0.40

- 0.60

- 0.80

- 1.00

- background rate = 200 per 105 person-years
- (AMI and CVA in adults 20-64 years)

**RR=1.5**

**RR=2**

**RR=3**

## Probability of excluding a given risk ratio, assuming true RR=1:  background = 15 per 105 person-years(AMI in children age 1-19)

**RR=2**    
**RR=3**    
**RR=5**    ▲

## Probability of excluding a given risk ratio, assumingtrue RR=1:  background = 3 per 105 person-years(CVA in children age 1-19)

**RR=2    ******
**RR=3   **** ******
**RR=5    ****▲**
**RR=10  ****●**

## Probability of excluding a given risk ratio, assumingtrue RR=1:  background = 200 per 105 person-years(AMI or CVA in adults age 20-64)

**RR=2    ******
**RR=3   **** ******

## Estimated risk ratio that might be detected with  80% probability by age- and drug-group

- AMI: acute myocardial infarction
- CVA: cerebrovascular accident (stroke)

## Some additional power considerations

- AMI: acute myocardial infarction
- CVA: cerebrovascular accident (stroke)

## Caveats

- Preliminary results
- Crude definitions of exposure, outcome
- Hospital D/C diagnoses, not validated
- Outcome post 1st Rx; relation to current use not known
- Out of hospital deaths (SCD) captured at only 1 site
- Comorbidities broadly defined
- Could shift with refinement during in-depth study
- Relationship to outcomes with respect to age not known
- Power calculations crude
- Some uncertainty regarding background rates

## Summary

- Potential for CV risk with ADHD drugs
- High prevalence of use in children; growing in adults
- Sudden unexplained death of 1 interest; most difficult to study
- TN Medicaid and KPRI have death certificate linkage
- TN data can go back ~20 years; KPRI ~8 years
- Other sites would require NDI search
- Other CV outcomes
- Feasibility study
- Exposed person-time substantial for most ADHD drugs
- CV outcomes require validation; timing with respect to exposure
- Power probably sufficient to address several outcomes
- Number of arrhythmia cases seems surprisingly high

## FDA Epidemiology Contracts ADHD Study Team (listed by site)

- FDA, ODS
- Kate Gelperin, MD, MPH
- Andrew Mosholder, MD, MPH
- David J. Graham, MD, MPH
- Judy A. Staffa, PhD
- HMO Research Network
- Susan E. Andrade, PhD
- Ingenix (i3 Drug Safety)
- K. Arnold Chan, MD, ScD
- Kaiser Permanente Research Institute
- Joe Selby, MD, MPH
- Medicaid (TN and WA)
- William Cooper, MD, MPH