# Presentation: 701185

## ADHD drugs and CV outcomes: Preliminary feasibility resultsand potential observational studies

- David J. Graham, MD, MPH
- on behalf of the FDA
- Epidemiology Contracts Study Team
- March 22, 2006

## FDA’s Epidemiology Contracts Program

- Replaces Cooperative Agreement Program
- Provides capability to study safety questions in a population setting
- 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

## Details of ADHD drug exposure cohortsof children ≤ 19 years

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

**Methylphenidate**  

**Amphetamine**  

**Atomoxetine**  

## Background rates for cardiovascular events 

- Background rates for cardiovascular events
- of interest in pediatric population age 1-19

## Counts of potential study outcomesin children age 1-19 years,

- Counts of potential study outcomesin children age 1-19 years,
- based on hospital discharge diagnoses

## Deaths reported within pediatric ADHD-drug-exposed inception cohorts

-   Deaths occurred at any time after cohort entry
-   From any cause
-   In-hospital only from 2 sites, none 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, $$

## 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**

## Event number and statistical power required

**RR=2**

**RR=3**

**RR=5**

**RR=10**

- to confirm risk ratios from 2 to 10

## 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=10**

**RR=5**

**RR=3**

**RR=2**

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

## Some additional power considerations

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

## Caveats regarding ADHD cohort study

***Preliminary data***; relationship of drug exposures to outcomes not yet studied
- Crude definitions of exposure, outcome
- Hospital D/C diagnoses, not validated
- Outcome post 1st Rx; timing with current use not known
- Out of hospital deaths (SCD) not captured at 2 sites
- Power calculations crude
- Uncertainty regarding background rates (i.e., AMI)

## Proposal offered at February advisory meeting

- Observational echocardiographic study
- Within a large healthcare database:
- Identify patients treated with ADHD drugs for varying durations of time
- Select suitable untreated “controls” from same population
- Perform echocardiography and assess
- Left ventricular wall thickness
- Contractility

## Patient sampling for echocardiographic study

**Methylphenidate**  

**Amphetamine**  

**Atomoxetine**  

## Summary

- Concern regarding potential for CV risk of 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
- 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
- Statistical power and uncertainty
- Number of arrhythmia cases seems surprisingly high
- Now in process of obtaining cost estimates for in-depth study

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

- FDA, ODS
- Andrew Mosholder, MD, MPH
- Kate Gelperin, MD, MPH
- Judy A. Staffa, PhD
- David J. Graham, MD, MPH
- 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